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Genome-wide analysis showed that putative G-quadruplex DNA structures are prevalent in the human genome. The presence of G-quadruplex structure in the telomere and promoter region of certain oncogenes inspired people to use G-quadruplex ligand as anti-cancer agents. G-quadruplex structures, stabilized by ligand at telomere are resolved by telomerase making the cancer cells resistant to G-quadruplex ligand. So, identification of a new G-quadruplex ligand having anti-telomerase activity would be a promising strategy for cancer therapy as about 85% of human cancers are telomerase positive. A set of the drug-like compounds were screened from the ZINC database randomly and 2284 ligands were chosen following Lipinski’s rule of five that were docked with five different G-quadruplex DNA sequences in idock. We screened 43 potential G-quadruplex binders using Z-score as a normalization scoring function. The compound (ZINC ID-05220992) gave the best score (average idock = −10.17 kcal/mol, average normalized idock = −3.42). We performed G4 FID assay, CD analysis to understand its binding with three different G-quadruplex DNA sequences, and checked its anti-telomerase activity in A549 cells using TRAP assay. We observed that this compound had an intrinsic fluorescence, capability to stain live cells with a blue fluorescence, and a specific affinity to only 22AG out of three different G-quadruplex DNA sequences under study. It showed cytotoxicity, good permeability to live cells, and a significant reduction of telomerase activity in human A549 cells at a very low dose. So, this compound has strong potential to be an anti-cancer drug.Graphical AbstractHighlightsA set of compounds were screened randomly by a High throughput method and Lipinski’s rule of five from ZINC database to identify potential G4-binders.The compound (ZINC ID-05220992) was screened after docking with five G-quadruplex DNAIt binds G-quadruplex DNA 22AG as detected by TO displacement and CD spectroscopy.It inhibits telomerase activity in A549 cells and also cytotoxic to this cell.It penetrates live A549 cell in culture and stains it with blue fluorescence

Modulation of proteasome function by pharmacological interventions and molecular biology tools is an active area of research in cancer biology and neurodegenerative diseases. Curcumin (diferuloylmethane) is a naturally occurring polyphenol that affects multiple signaling pathways and known to modulate PKC activities. The therapeutic significance of curcumin is often considered to reside in its anti-inflammatory, antioxidant, anti-angiogenic, or anti-apoptotic properties. However, recent research suggests that the therapeutic efficacy of curcumin may be due to its activity as a potent inhibitor of the proteasome. In this study, we show that both curcumin and its synthetic polyphenolic derivative (didemethylcurcumin), CUIII modulated proteasome activity in a biphasic manner. Curcumin and CUIII increased proteasome activity at nanomolar concentrations but inhibited proteasome activity at micromolar concentrations. Curcumin was more effective than CUIII in relative proteasome activity increase at nanomolar concentrations. Also, curcumin was more effective than CUIII in relative proteasome activity inhibition at micromolar concentration. The docking study was conducted on the 20S proteasome catalytic subunit. Estimated Kd values for curcumin and didemethylcurcumin are 0.0054μM and 1.3167μM, respectively. These values correlate well with the results of the effectiveness of modulation by curcumin compare to CUIII. The small size of CUIII makes its dock to the narrow cavity of the active site, but the binding interaction is not strong compare to curcumin. This study suggests that curcumin and its didemethyl derivative can be used to modulate proteasome activity. This communication implicates the reason why curcumin and its didemethyl derivative can be used to two different disease mechanisms, neurodegeneration, and cancer.

Background Multi-drug resistance tuberculosis is chronic and highly affected to mankind. Millions of people are affected by tuberculosis and lost their lives every year. Mycobacterium tuberculosis is resistant to the most commonly used anti-TB drugs, hence new drugs need to be developed in a short time. In this direction, many chemical compounds including benzimidazole derivatives have been identified as potent anti-tb agents. Method Various benzimidazole derivatives were subjected to in-silico computational screening to identify the potent anti-tubercular analogues. The ADME pharmacokinetics evaluation was performed to identify the drug-like molecules. Molecular docking investigation of selected compounds was performed against Mycobacterium Tuberculosis Enoyl Reductase (Inha) with PDB ID: 2B37 , 1QG6 , 4TZK , and 4TZK . The common pharmacophore hypothesis was generated using the molecular docking post-processing module. Result The result of ADME pharmacokinetics of some compounds is very close to the drug-like properties and can be developed as good inhibitors. Molecular docking study suggests that the proposed benzimidazole and 4H-pyran derivative have better binding affinity than standard and triclosan derivatives. Results from the pharmacophore hypothesis development study also support and suggest our prediction regarding the minimum pharmacophore features required in ligands to behave as a Mycobacterium Tuberculosis inhibitor. Conclusion Coumarin, phenylurea clubbed benzimidazole moiety and pyrano[2,3-c]pyrazole derivatives have shown greater selectivity and potency towards Mycobacterium Tuberculosis. By employing a combination of ADME, docking, and pharmacophore study calculations, novel potent hits to inhibit enoyl-acp reductase were identified with the points for consideration for designing of enoyl-acp reductase inhibitor.

Background: Hexahydroquinoline as a small molecule was reported for good cytotoxicity and affinity towards Mcl-1. Hence, new compounds were explored as Mcl-1 inhibitors to be potent anticancer agents. Objective: Compounds were synthesized and screened for cytotoxicity. The active compound was evaluated for cell cycle analysis, Mcl-1 inhibition, caspase-3, and caspase-9 activation. Further compounds were docked with Mcl-1 to confirm the mechanism of cytotoxicity. Methods: Compounds were confirmed by spectral techniques and screened for cytotoxicity at National Cancer Institute (USA). The active derivatives were screened by SRB and MTT. In addition, the potent compound was studied for apoptosis and cell cycle analysis by PI staining, Mcl-1 inhibition by TR-FRET assay, and activation assay of caspase-3 and caspase-9 with the Elisa technique. Results: Compounds 6a and 6b exhibited the highest growth inhibition of 86.28% and 93.20% against SR and HOP- 62, respectively. Compound 6a showed higher cytotoxicity (IC50 = 0.4 μM) against THP-1 and HL-60. It showed 15- fold higher apoptosis compared to control by arresting cells at the Sub-G1 in the cell cycle. It also showed a potent inhibition with IC50 of 1.5 μM against the anti-apoptotic protein Mcl-1, which may induce apoptosis. Furthermore, apoptosis was evidenced by an increase in cleaved caspase-3 and caspase-9 to 4.20 and 3 folds, respectively higher than control. The docking score of compound 6a was in good agreement with the Mcl-1 inhibition assay. Conclusion: Compound 6a inhibited anti-apoptotic protein Mcl-1 and induced activation of pro-apoptotic proteins caspase-3 and caspase-9. These dual results suggested the mechanism of apoptosis and cytotoxicity.

With the gradual increase in the COVID-19 mortality rate, there is an urgent need for an effective drug/vaccine. Several drugs like Remdesivir, Azithromycin, Favirapir, Ritonavir, Darunavir, etc., are put under evaluation in more than 300 clinical trials to treat COVID-19. On the other hand, several vaccines like Pfizer-BioNTech, Moderna, Johnson & Johnson’s Janssen, Sputnik V, Covishield, Covaxin, etc., also evolved from the research study. While few of them already gets approved, others show encouraging results and are still under assessment. In parallel, there are also significant developments in new drug development. But, since the approval of new molecules takes substantial time, drug repurposing studies have also gained considerable momentum. The primary agent of the disease progression of COVID-19 is SARS-CoV2/nCoV, which is believed to have ∼89% genetic resemblance with SARS-CoV, a coronavirus responsible for the massive outbreak in 2003. With this hypothesis, Human-SARS-CoV protein interactions are used to develop an in-silico Human-nCoV network by identifying potential COVID-19 human spreader proteins by applying the SIS model and fuzzy thresholding by a possible COVID-19 FDA drugs target-based validation. At first, the complete list of FDA drugs is identified for the level-1 and level-2 spreader proteins in this network, followed by applying a drug consensus scoring strategy. The same consensus strategy is involved in the second analysis but on a curated overlapping set of key genes/proteins identified from COVID-19 symptoms. Validation using subsequent docking study has also been performed on COVID-19 potential drugs with the available major COVID-19 crystal structures whose PDB IDs are: 6LU7, 6M2Q, 6W9C, 6M0J, 6M71 and 6VXX. Our computational study and docking results suggest that Fostamatinib (R406 as its active promoiety) may also be considered as one of the potential candidates for further clinical trials in pursuit to counter the spread of COVID-19.

Background: Indoline-2,3-dione comprises a leading course group of heterocycles endowed with appealing biological actions, including anticancer activity. There are significant justifications for exploring the anticancer activity of Schiff base derivatives of isatin as a vast number of reports have documented remarkable antiproliferative action of isatin nucleus against various cancer cell lines. Aims and Objectives: A series of arylthiazole linked 2H-indol-2-one derivatives (5a-t) was designed and synthesized as potential VEGFR-2 kinase inhibitors keeping the essential pharmacophoric features of standard drugs, like sunitinib, sorafenib, nintedanib, etc. They were evaluated for their in vitro anticancer activity. The aim of this study was to investigate and assess the anticancer potential of isatin-containing compounds along with their kinase inhibition activity. Methods: The title compounds were synthesized by reacting substituted isatins with para-substituted arylthiazoles using appropriate reaction conditions. Selected synthesized derivatives went under preliminary screening against a panel of 60 cancer cell lines at NCI, the USA, for single-dose and five dose assays. Molecular docking was performed to explore the binding and interactions with the active sites of the VEGFR-2 receptor (PDB Id: 3VHE). Derivatives 5a, 5b, 5c, 5d, 5g, 5h, and 5m were assessed for in vitro inhibition potency against Human VEGFR-2 using ELISA (Enzyme- Linked Immunosorbent Assay) kit. All the target compounds were determined against human colon cancer cell line SW480 (colorectal adenocarcinoma cells). Cellular apoptosis/necrosis was determined by flow cytometry using annexin V-FITC. DNA content of the cells was analyzed by flow cytometry and the cycle distribution was quantified. Results: Compounds 5a and 5g exhibited noteworthy inhibition during a five-dose assay against a panel of 60 cell lines with MID GI50 values of 1.69 and 1.54 μM, respectively. Also, both the lead compounds 5a and 5g demonstrated promising VEGFR-2 inhibitory activity with IC50 values of 5.43±0.95 and 9.63±1.32 μM, respectively. The aforesaid potent compounds were found effective against SW480 (colorectal adenocarcinoma cells) with IC50 values of 31.44 μM and 106.91 μM, respectively. Compound 5a was found to arrest the cell cycle at the G2/M phase, increasing apoptotic cell death. The docking study also supported VEGFR-2 inhibitory activity as both compounds 5a and 5g displayed promising binding and interactions with the active sites of VEGFR-2 receptor (PDB: 3VHE) with docking scores - 9.355 and -7.758, respectively. All the compounds obeyed Lipinski’s rule of five. Conclusion: Indoline-2,3-dione and thiazole have huge potential to be considered a steer combination approach for developing promising kinase inhibitors as cancer therapeutics.

Hypertension, or elevated arterial blood pressure, is a substantial public health problem. The two 11β-hydroxysteroid dehydrogenase (11β-HSD) isozymes catalyze the interconversion of cortisol and cortisone. Inhibition of two 11β-hydroxysteroid dehydrogenase (11β-HSD) enzymes present the key in the disease of arterial hypertension 1(PAH) treatment actually an important number of synthetics inhibitors of this enzyme were studied. However Triazoles synthetic inhibitors were identified as the most efficient ones, indeed, the most commercialized treatment of arterial hypertension 1 is Triazoles. The research and synthesis of new pharmacologically active molecules is the subject of a theoretical study by molecular modeling. Our research consists in studying the inhibition of the enzymes applied in the disease of arterial hypertension 11-beta-hydroxysteroid dehydrogenase of type 1 and type 2 with some derivatives of 1,2,4-triazoles by means of molecular docking and molecular dynamics approaches. Theoretical calculation was done using a MOE program for molecular docking and HyperChem and others softwares were used to find the best compounds with high affinity. The interactions between the studied inhibitors and our target were further explored through molecular docking and molecular dynamics simulations, in the presence of water molecules. The molecular dynamics study was done for the best derivatives of 1,2,4-triazoles inhibitors (deducted from the docking best scores for L2 and L1, and lowest score for Lref). A few key residues ( N-14 with oxygen receptor interaction H- donor) at the binding site of 11-beta-hydroxysteroid dehydrogenase of type 1 (11β-HSD1) and type2 (11β-HSD2) were identified. Obtained Docking and molecular dynamics result, both leads to the same conclusion and predict that L2 subsisted derivatives of 1, 2, 4-triazoles is the best inhibitor candidate.

Background: T-type calcium channels are aberrantly expressed in different human cancers and regulate cell cycle progression, proliferation, migration, and survival. FAK-1 can promote tumor protein degradation (p53) through ubiquitination, leading to cancer cell growth and proliferation. Similar findings are obtained regarding protease inhibitors' effect on cytokine-induced neutrophil activation that suppresses Granulocyte-macrophage colony-stimulatingfactor (GM-CSF) TNF-α-induced O2 release and adherence in human neutrophils without affecting phosphorylation of Extracellular signal-regulated kinase (ERK) and p38. Nanosuspensions are carrier-free, submicron colloidal dispersions, which consist of pure drugs and stabilizers. Incorporating drug loaded in nanosuspensions offer a great advantages of passive drug targeting with improved solubility, stability, and bioavailability, as well as lower systemic toxicity. Objective: The present investigation objective was to establish a molecular association of Protease and Focal Adhesion Kinase 1 as cancer targets for isradipine, a calcium channel blocker (CCB). Furthermore, the study also aimed to formulate its optimized nanosuspension and how the physical, morphological, and dissolution properties of isradipine impact nanosuspension stability. Material and Method: Five different molecular targets, namely Cysteine Proteases (Cathepsin B), Serine Proteases (Matriptase), Aspartate Proteases, Matrix Metalloproteases (MMP), and FAK-1 were obtained from RCSB-PDB, which has some potential associations with inhibition in cancer pathogenesis. Molecular interactions of these targets with CCB isradipine were identified and established by molecular simulation docking studies. Isradipine-loaded nanosuspension was prepared by precipitation technique by employing a 23 factorial design. PVP K-30, poloxamer 188, and sodium lauryl sulfate (SLS) were used as polymer, co-polymer, and surfactant, respectively. The nanosuspension particles were assessed for particle size, zeta potential, viscosity, polydispersity index (PDI), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), In-vitro drug release kinetics, and short-term stability study. Result: Considerable interactions were found with Cysteine, Serine, Aspartate, Threonine, and Matrix metalloproteases with binding energies of -3.91, -6.7, -3.48, -8.42, respectively. Furthermore, the interaction of isradipine with FAK-1 was compared with 7 native ligands and was found to show significant interaction with binding energies of - 8.62, -7.27, -7.69, -5.67, -5.41, -7.44, -8.21, respectively. The optimized nanosuspension was evaluated and exhibited a particle size of 754.9 nm, zeta potential of 32.5 mV, viscosity of 1.287 cp, and PDI of 1.000. The In-vitro dissolution of the optimized formulation (F8) was found to be higher (96.57%) as compared to other formulations Conclusion: Isradipine could act as a potential inhibitor of different proteases and FAK-1 associated with tumor growth initiation, progression, and metastasis. Furthermore, isradipine-loaded nanosuspension with optimized release could be utilized to deliver the anticancer drug in a more targeted way as emerging cancer nanotechnology.

Background: Inducible nitric Oxide Synthase (iNOS) plays a key role in the progression of inflammatory diseases by accelerating the production of NO, which makes it an intriguing target to treat inflammation in complex diseases. Therefore, the search is on to develop molecules as selective iNOS inhibitors. Objective: The present work was aimed to design, synthesize and evaluate benzimidazole-coumarin coupled molecules as anti-iNOS agents through in silico and pharmacological studies. Methods: A critical study of literature reports on iNOS inhibitors led to the selection of a (un)substituted coumarin nucleus, 2-aminobenzimidazole, and a 4-atom linker as important structural components for iNOS inhibition. Two series of compounds (7-16 and 17-26) were designed and synthesized by coupling these components. The compounds were subjected to docking using iNOS (1QW4) and nNOS (1QW6) as targets. All compounds were evaluated for NO and iNOS inhibitory activities in vitro. The selected compound was finally evaluated for anti-inflammatory activity in vivo using the carrageenan-induced rat paw edema model. Results: All compounds showed moderate to good inhibition of NO and iNOS in vitro. Compound 12 was the most potent inhibitor of NO and iNOS. Hence, it was evaluated in vivo for toxicity and anti-inflammatory activity. It was found to be safe in acute toxicity studies, and effective in reducing the rat paw edema significantly. Its anti-inflammatory behaviour was similar to that of aminoguanidine, which is a selective iNOS inhibitor. Conclusion: The newly synthesized benzimidazole-coumarin hybrids may serve as potential leads for the development of novel anti-iNOS agents.

Background: Parkinson’s Disease (PD) exhibits the extrapyramidal symptoms caused due to the dopaminergic neuronal degeneration in the substantia nigra of the brain and depletion of Aldehyde Dehydrogenase (ALDH) enzyme. Objective: This study was designed to enlighten the importance of the Aldehyde dehydrogenase enzyme in protecting the dopamine levels in a living system. Camalexin, a potentially active compound, has been evaluated for its dopamine enhancing and aldehyde dehydrogenase protecting role in pesticide-induced Parkinson’s disease. Methods: AutoDock 4.2 software was employed to perform the docking simulations between the ligand camalexin and standard drugs Alda-1, Ropirinole with three proteins 4WJR, 3INL, 5AER. Consequently, the compound was evaluated for its in vivo neuroprotective role in the zebrafish model by attaining Institutional Animal Ethical Committee permission. The behavioral assessments and catecholamine analysis in zebrafish were performed. Results: The Autodock result shows that the ligand camalexin has a lower binding energy (-3.84) that indicates a higher affinity with the proteins when compared to the standard drug of proteins (-3.42). In the zebrafish model, behavioral studies provided evidence that camalexin helps in the improvement of motor functions and cognition. The catecholamine assay has proved that there is an enhancement in dopamine levels, as well as an improvement in aldehyde dehydrogenase enzyme. Conclusion: The novel compound, camalexin, offers a protective role in Parkinson’s disease model by its interaction with neurochemical proteins and also in alternative in vivo model.

Background: Integrase enzyme is a validated drug target to discover novel structures as anti-HIV-1 agents. Objective: This study aimed at developing a novel series of thioimidazolyl diketoacid derivatives characterizing various substituents at N-1 and 2-thio positions of the central ring as HIV-1integrase inhibitors. Methods: In this study, eighteen novel thioimidazolyl DKA derivatives were synthesized in a fivestep parallel procedure and tested in vitro for the inhibition of both IN ST reaction and the singlecycle HIV-1 replication in HeLa cell culture. Results: The obtained molecules were evaluated using the enzyme assay, displaying promising integrase inhibitory activity with IC50 values ranging from 0.9 to 7.7 mM. The synthesized compounds were also tested for antiviral activity and cytotoxicity using HeLa cells infected by the single-cycle replicable HIV-1 NL4-3. Conclusion: The most potent compound was found to be 18i with EC50 = 19 μM, IC50 = 0.9 μM, and SI = 10.5. Docking studies indicated that the binding mode of the active molecule is well aligned with the known HIV-1integrase inhibitor.

Glycoside hydrolase family 31 (GH31) is a diversified family of anomer-retaining α-glycoside hydrolases, such as α-glucosidase and α-xylosidase, among others. Recently, GH31 α-N-acetylgalactosaminidases (Nag31s) have been identified to hydrolyze the core of mucin-type O-glycans and the crystal structure of a gut bacterium Enterococcus faecalis Nag31 has been reported. However, the mechanisms of substrate specificity and hydrolysis of Nag31s are not well investigated. Herein, we show that E. faecalis Nag31 has the ability to release N-acetylgalactosamine (GalNAc) from O-glycoproteins, such as fetuin and mucin, but has low activity against Tn antigen. Mutational analysis and crystal structures of the Michaelis complexes reveal that residues of the active site work in concert with their conformational changes to act on only α-N-acetylgalactosaminides. Docking simulations using GalNAc-attached peptides suggest that the enzyme mainly recognizes GalNAc and side chains of Ser/Thr, but not strictly other peptide residues. Moreover, quantum mechanics calculations indicate that the enzyme preferred p-nitrophenyl α-N-acetylgalactosaminide to Tn antigen and that the hydrolysis progresses through a conformational itinerary, 4C1 → 1S3 → 4C1, in GalNAc of substrates. Our results provide novel insights into the diversification of the sugar recognition and hydrolytic mechanisms of GH31 enzymes.

Background: CDK2 participates in the control of eukaryotic cell-cycle progression. Due to the great interest in CDK2 for drug development and the relative easiness in crystallizing this enzyme, we have over 400 structural studies focused on this protein target. This structural data is the basis for the development of computational models to estimate CDK2-ligand binding affinity. Objective: This work focuses on the recent developments in the application of supervised machine learning modeling to develop scoring functions to predict the binding affinity of CDK2. Method: We employed the structures available at the protein data bank and the ligand information accessed from the BindingDB, Binding MOAD, and PDBbind to evaluate the predictive performance of machine learning techniques combined with physical modeling used to calculate binding affinity. We compared this hybrid methodology with classical scoring functions available in docking programs. Results: Our comparative analysis of previously published models indicated that a model created using a combination of a mass-spring system and cross-validated Elastic Net to predict the binding affinity of CDK2-inhibitor complexes outperformed classical scoring functions available in AutoDock4 and AutoDock Vina. Conclusion: All studies reviewed here suggest that targeted machine learning models are superior to classical scoring functions to calculate binding affinities. Specifically for CDK2, we see that the combination of physical modeling with supervised machine learning techniques exhibits improved predictive performance to calculate the protein-ligand binding affinity. These results find theoretical support in the application of the concept of scoring function space.

Background: Many natural and synthetic flavonoids have been studied and documented by inhibiting aromatase enzymes for their anti-cancer activity against breast carcinoma. The aromatase enzyme is a possible target for the estrogen's positive breast cancer receptor. Objective: Hence, a series of flavonoids have been synthesized and assessed for their in vitro cytotoxicity and aromatase inhibitory activity. Methods: 39 Flavonoids were synthesized and characterized by spectroscopic techniques, and their computational study was performed using the maestro version of the Schrodinger. In-silico ADME properties were checked by QikProp software. A total of 18 compounds were evaluated based on the docking score using cytotoxicity assay in human breast cancer cell line MCF-7. Results: Of the 18 compounds tested, 07 compounds, namely 2b, 8b, 14b, 15b, 19b, 24b, and 30b flavonoids were found to be more active with their IC50 values of 20.73 μM, 1.636 μM, 16.08 μM, 22.02 μM, 15.75 μM, 0.345 μM and 16.08 μM, respectively, compared with the reference drug letrozole. The in-vitro aromatase inhibitory activity of six compounds 2b, 8b, 14b, 19b, 24b, and 30b was conducted using a fluorogenic assay kit. The values of IC50 for compounds 2b and 24b were found to be 0.31 μM and 0.36 μM, respectively. Conclusion: Therefore, it was concluded that compounds 2b and 24b had a potent inhibitory effect of aromatase compared with letrozole with an IC50 value of 0.86 μM. At the same time, the other compounds 8b, 14b, 30b, and 19b were considered to have similar aromatase inhibitory activity. Hence, their essential aromatase inhibitory activities make them good lead candidates for developing potent inhibitors of aromatase.

Background: Hepatitis C virus (HCV) is an enveloped and positive-stranded RNA virus that is a major causative agent of chronic liver diseases worldwide. HCV has become the main cause of liver transplantations and there is no effective drug for all hepatitis genotypes. Elucidation of life cycle and nonstructural proteins of HCV involved in viral replication are the attractive targets for the development of antiviral drugs. Methods: In this work, pharmacoinformatics approaches coupled with docking analyses were applied on HCV nonstructural proteins to identify the novel potential hits and HCV drugs. Molecular docking analyses were carried out on HCV approved drugs followed by the ligand-based pharmacophore generation to screen the antiviral libraries for novel potential hits. Results: Virtual screening technique has made known the top-ranked five novel compounds (ZINC00607900, ZINC03635748, ZINC03875543, ZINC04097464, and ZINC12503102) along with the least binding energy (-8.0 kcal/mol, -6.1 kcal/mol, -7.5 kcal/mol, -7.4 kcal/mol, and -7.3 kcal/mol respectively) and stability with non-structural proteins target. Conclusion: These promising hits exhibited better absorption and ADMET properties as compared to the selected drug molecules. These potential compounds extracted from in silico approach may be significant in drug design and development against Hepatitis and other liver diseases.

The epidemic of the novel coronavirus disease (COVID-19) that started in 2019 has evoked an urgent demand for finding new potential therapeutic agents. In this study, we performed a molecular docking of anti-HIV drugs to refine HIV protease inhibitors and nucleotide analogues to target COVID-19. The evaluation was based on docking scores calculated by AutoDock Vina and top binding poses were analyzed. Our results suggested that lopinavir, darunavir, atazanavir, remdesivir, and tipranavir have the best binding affinity for the 3-chymotrypsin-like protease of COVID-19. The comparison of the binding sites of three drugs, namely, darunavir, atazanavir and remdesivir, showed an overlap region of the protein pocket. Our study showed a strong affinity between lopinavir, darunavir, atazanavir, tipranavir and COVID-19 protease. However, their efficacy should be confirmed by in vitro studies since there are concerns related to interference with their active sites.

Nucleic acid (NA)–ligand interactions have crucial roles in many cellular processes and, thus, are increasingly attracting therapeutic interest in drug discovery. Molecular docking is a valuable tool for studying molecular interactions. However, because NAs differ significantly from proteins in both their physical and chemical properties, traditional docking algorithms and scoring functions for protein–ligand interactions might not be applicable to NA–ligand docking. Therefore, various sampling strategies and scoring functions for NA–ligand interactions have been developed. Here, we review the basic principles and current status of docking algorithms and scoring functions for DNA/RNA–ligand interactions. We also discuss challenges and limitations of current docking and scoring approaches.

Purpose: To investigate the bio-active components and the potential mechanism of the prescription remedy, Han-Shi blocking lung, with network pharmacology with a view to expanding its application. Methods: Chemical components were first collected from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Pharmmapper database and GeneCards were used to predict the targets related to active components and COVID-19. Using DAVIDE and KOBAS 3.0 databases, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were enriched. A “components-targets-pathways” (C-T-P) network was conducted by Cytoscape 3.7.1 software. With the aid of Discovery Studio 2016 software, bio-active components were selected to dock with SARS-COV-2 3CL and ACE2. Results: From the prescription, 47 bio-active components, 83 targets and 103 signaling pathways were obtained in total (p < 0.05). 126 GO entries (p < 0.05) were screened by GO enrichment analysis. Molecular docking results showed that procyanidin B1 eriodictyol, (4E, 6E)-1, 7-bis(4- hydroxyphenyl)hepta-4, 6-dien-3-one, and quercetin had higher docking scores with SARS-COV-2 3CL and ACE2. Conclusion: With network pharmacology and molecular docking, the bio-active components and targets of this prescription, Han-Shi blocking lung, against COVID-19 were identified. Taken together, this study provided a basis for the treatment of COVID-19 and further promotion of this prescription.

Protein docking protocols typically involve global docking scan, followed by re-ranking of the scan predictions by more accurate scoring functions that are either computationally too expensive or algorithmically impossible to include in the global scan. Development and validation of scoring methodologies are often performed on scoring benchmark sets (docking decoys) which offer concise and nonredundant representation of the global docking scan output for a large and diverse set of protein-protein complexes. Two such protein-protein scoring benchmarks were built for the Dockground resource, which contains various datasets for the development and testing of protein docking methodologies. One set was generated based on the Dockground unbound docking benchmark 4, and the other based on protein models from the Dockground model-model benchmark 2. The docking decoys were designed to reflect the reality of the real-case docking applications (e.g., correct docking predictions defined as near-native rather than native structures), and to minimize applicability of approaches not directly related to the development of scoring functions (reducing clustering of predictions in the binding funnel and disparity in structural quality of the near-native and non-native matches). The sets were further characterized by the source organism and the function of the protein-protein complexes. The sets, freely available to the research community on the Dockground webpage, present a unique, user-friendly resource for the developing and testing of protein-protein scoring approaches.

Background: Iminostilbene and 1,2,3-triazole ring containing compounds are considered as beneficial substrates in drug design. Objectives: This study was aimed at the synthesis of novel series of iminostilbene linked 1,2,3- triazole pharmacophores (7c-n) by Cu(I) catalyzed 1,3 dipolar cycloaddition reaction between 5- (Prop-2-yn-1-yl)-5H-dibenzo[b,f]azepine (7b) and various substituted azidobenzene derivatives (3cn). Methods: The chemical structures of compounds were confirmed by 1H NMR, 13C NMR, LC-MS and molecular docking studies were carried out through HEX docking software. Results: The in vivo anti anxiety capacity of the compounds was evaluated by using “elevated plus maze” (EPM), anxiety model. The results exhibited that compounds (7d, 7e, 7j and 7k) have a higher anti anxiety effect close to diazepam. The anti-inflammatory activities of the synthesized compounds were evaluated by “Carrageenan-induced rat paw edema” model, compounds (7b, 7c, 7d, 7f, and 7j) demonstrated statistically significant inflammatory activity. Molecular docking analysis revealed that compounds (7d, 7e and 7j) bound to GABA(A) proteins show more efficiency when compared to the other analogues in the series. Conclusion: These results suggest that compounds (7b, 7c, 7d, 7e, 7f, and 7j) can be considered as novel candidates for anti-anxiety and anti-inflammatory agents. Moreover, docking method was used to elucidate anti-anxiety effect of compounds. This study furnished insight into the molecular interactions of synthesized compounds with their physiological targets, and the potential to develop bioactive heterocyclic compounds.

Background: The discovery of therapeutic anticancer agents based on natural products is one of the current research focuses. Network pharmacology will broaden our understanding of drug actions by bioinformatics analysis. Objective: To explore the potential and provide scientific evidence for methylaervine as a lead compound against cervical carcinoma. Methods: Methylaervine was synthesized, and its activity against four cancer cell lines was evaluated by MTT assay. Pharmacokinetic properties were obtained by in silico approaches, and the pharmacologic mechanism was predicted by network pharmacology. Then we validated and investigated our predictions of candidate targets using a molecular docking study. Results: Methylaervine was synthesized with a total yield of 54.9%, which displayed activity against HeLa (IC50 = 14.8 μM) with good predicted pharmacokinetic properties, thus it was considered a potential lead compound. The network pharmacology study indicated that methylaervine could act against cervical carcinoma by regulating the function of multiple pivotal targets, such as CTNNB1, PTPRJ, RPA1, and TJP1, mainly covering cell growth, cell motility, and cell proliferation. Moreover, docking analysis showed that hydrogen bonds and hydrophobic interactions were the main forms of interactions. Conclusion: This work would provide new insight into the design of anti-cervical carcinoma drugs based on methylaervine.

Background: Aedes aegypti is the primary dengue vector, a significant public health problem in many countries. Controlling the growth of Ae. aegypti is the biggest challenge in the mosquito control program, and there is a need for finding bioactive molecules to control Ae. aegypti in order to prevent dengue virus transmission. Objective: To assess the mosquitocidal property of lawsone and its 3-methyl-4H-chromen-3-yl-1-phenylbenzo[6,7]chromeno[2,3,c]pyrazole-dione derivatives (6a-6h) against various life stages of Ae. aegypti. Besides, to study the mode of action of the active compound by molecular docking and histopathological analysis. Methods: All derivatives were synthesized from the reaction between 2-hydroxy-1,4-naphthoquinone, chromene-3-carbaldehyde, and 1-phenyl-3-methyl-pyrazol-5-one by using one pot sequential multicomponent reaction. The mosquito life stages were subjected to diverse concentrations ranging from 1.25, 2.5, 5.0, and 10 ppm for lawsone and its derivatives. The structure of all synthesized compounds was characterized by spectroscopic analysis. Docking analysis was performed using autodock tools. Midgut sections of Ae. aegypti larvae were analyzed for histopathological effects. Results: Among the nine compounds screened, derivative 6e showed the highest mortality on Ae. aegypti life stages. The analyzed LC50 and LC90 results of derivative 6e were 3.01, 5.87 ppm, and 3.41, 6.28 ppm on larvae and pupae of Ae. aegypti, respectively. In the ovicidal assay, the derivative 6e recorded 47.2% egg mortality after 96-hour post-exposure to 10 ppm concentration. In molecular docking analysis, the derivative 6e confirmed strong binding interaction (-9.09 kcal/mol and -10.17 kcal/mol) with VAL 60 and HIS 62 of acetylcholinesterase 1 (AChE1) model and LYS 255, LYS 263 of kynurenine aminotransferase of Ae. aegypti, respectively. The histopathological results showed that the derivative 6e affected the columnar epithelial cells (CC) and peritrophic membrane (pM). Conclusion: The derivative 6e is highly effective in the life stages of Ae. aegypti mosquito and it could be used in the integrated mosquito management programme.

Background: Thiobezimidazoles reveal various pharmacological activities due to similarities with many natural and synthetic molecules, they can easily interact with biomolecules of living systems. Objective: A series of substituted 2-thiobezimidazoles has been synthesized .Twelve final compounds were screened for in vitro anti-cancer activities against sixty different cell-lines. Methods: The spectral data of the synthesized compounds were characterized. Docking study for active anticancer compounds and CDK2/CyclinA2 Kinase assay against standard reference; Imatinib were performed. Results: Two compounds (3c&3l) from the examined series revealed effective antitumor activity in vitro against two-cancer cell lines (Colon Cancer (HCT-116) and Renal Cancer (TK-10). The docking study of synthesized molecules discovered a requisite binding pose in CDK-ATP binding pocket. 3c &3l were promoted in the CDK2/CyclinA2 Kinase assay against standard reference Imatinib. Conclusion: Against all tested compounds ; two compounds 3c &3l were found active against two types of cell-lines.

Objective: The research work aims synthesis of novel series of hydrazones, antioxidant screening, evaluate the binding affinities, and in silico methods for the identification of possible drug targets of synthesized compounds. Methods: This report briefly explains the synthesis of novel series of hydrazones was synthesized via. hydrazinolysis of esters to obtain hydrazide, treated with aldehyde and acetophenone to get hydrazones. The spectral confirmed hydrazones exhibited excellent to comparable anti-oxidant as compaired to the standard drugs Butylated hydroxytoluene (BHT) and Ascorbic acid. Molecular docking on myeloperoxidase (MPO) demonstrated the ability of this scaffold to correctly recognize the target and engage in significant bonded and non-bonded interactions with key residues therein. Results and Discussion: In this study, we report an effectively synthesized compounds BK-35, BK-41, BK-26, BK-28 and BK-39 showed the best DPPH radical scavenging activity. The docking results clearly showed the binding mode of hydrazones into the active site of Myeloperoxidase (MPO). An in-silico results, no any of the synthesized compounds BK24 to BK-41 violated Lipinski’s rule of five (miLog P ≤ 5). Conclusions: In vitro preliminary antioxidant screening results in support by in Silico binding affinity data of novel hydrazones of levofloxacin related molecules BK-24 to BK-41 reported here have emerged as excellent antioxidant agents. The inference derived from the in vitro antioxidant screening data and the quantitative insights derived from the per-residue interaction analysis with MPO enzyme, are now being fruitfully utilized for site specific mutation around the nucleus to identify selective and potent antioxidants.

Background: Diabetes mellitus is a chronic metabolic disorder, characterized by hyperglycemia over a prolonged period, disturbance of fat, protein and carbohydrate metabolism, resulting from defective insulin secretion, insulin action or both. Dipeptidyl peptidase-IV (DPP-IV) inhibitors are relatively a new class of oral hypoglycemic agents that reduces the deterioration of gut-derived endogenous incretin hormones that are secreted in response to food ingestion to stimulate the secretion of insulin from beta cells of pancreas. Objective: In this study, synthesis, characterization, and biological assessment of twelve novel phenanthridine sulfonamide derivatives 3a-3l as potential DPP-IV inhibitors was carried out. The target compounds were docked to study the molecular interactions and binding affinities against DPP-IV enzyme. Methods: The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and MS. Quantum-polarized ligand docking (QPLD) was also performed. Results: In vitro biological evaluation of compounds 3a-3l reveals comparable DPP-IV inhibitory activities ranging from 10%-46% at 100 µM concentration, where compound 3d harboring ortho-fluoro moiety exhibited the highest inhibitory activity. QPLD study shows that compounds 3a-3l accommodate DPP-IV binding site and form H-bonding with the R125, E205, E206, S209, F357, R358, K554, W629, S630, Y631, Y662, R669 and Y752 backbones. Conclusion: In conclusion, phenanthridine sulfonamides could serve as potential DPP-IV inhibitors that require further structural optimization in order to enhance their inhibitory activity.

Background: Malaria is caused by different species of Plasmodium; among which P. falciparum is the most severe. Coptis teeta is an ethnomedicinal plant of enormous importance for tribes of north east India. Objective: In this study, the anti malarial activity of the methanol extracts of Coptis teeta was evaluated in vitro and lead identification via in silico study. Method: On the basis of the in vitro results, in silico analysis by application of different modules of Discovery Studio 2018 was performed on multiple targets of P. falciparum taking into consideration some of the compounds reported from C. teeta. Results: The IC50 of the methanol extract of Coptis teeta 0.08 µg/ml in 3D7 strain and 0.7 µg/ml in Dd2 strain of P. falciparum. From the docking study, noroxyhydrastatine was observed to have better binding affinity in comparison to chloroquine. The binding of noroxyhydrastinine with dihydroorotate dehydrogenase was further validated by molecular dynamics simulation and was observed to be significantly stable in comparison to the co-crystal inhibitor. During simulations it was observed that noroxyhydrastinine retained the interactions, giving strong indications of its effectiveness against the P. falciparum proteins and stability in the binding pocket. From the Density-functional theory analysis, the band gap energy of noroxyhydrastinine was found to be 0.186 Ha indicating a favourable interaction. Conclusion: The in silico analysis as an addition to the in vitro results provide strong evidence of noroxyhydrastinine as an anti malarial agent.

Background: The Covid-19 virus emerged a few months ago in China and infections rapidly escalated into a pandemic. Objective: To date, there is no selective antiviral agent for the management of pathologies associated with covid-19 and the need for an effective agent against it is essential. Method: In this work two home-made databases from synthetic quinolines and coumarins were virtually docked against viral proteases (3CL and PL), human cell surface proteases (TMPRSS2 and furin) and spike proteins (S1 and S2). Chloroquine, a reference drug without a clear mechanism against coronavirus was also docked on mentioned targets and the binding affinities compared with title compounds. Result: The best compounds of synthetic coumarins and quinolines for each target were determined. All compounds against all targets showed binding affinity between -5.80 to -8.99 kcal/mol in comparison with the FDA-approved drug, Chloroquine, with binding affinity of -5.7 to -7.98 kcal/mol. Two compounds, quinoline-1 and coumarin-24, were found to be effective on three targets – S2, TMPRSS2 and furin – simultaneously, with good predicted affinity between -7.54 to -8.85 kcal/mol. In silico ADME studies also confirmed good oral absorption for them. Furthermore, PASS prediction was calculated and coumarin-24 had higher probable activity (Pa) than probable inactivity (Pi) with acceptable protease inhibitory as well as good antiviral activity against Hepatitis C virus (HCV), Human immunodeficiency virus (HIV) and influenza. Conclusion: Quinoline-1 and Coumarin-24 have the potential to be used against Covid-19. Hence these agents could be useful in combating covid-19 infection after further in vitro and in vivo studies.

A convenient and efficient synthesis of a series of ethyl-1-(6-(4-substitutedacetylatedpiperazin-1-yl)pyrimidin-4-yl)-5-amino-1H-pyrazole-4-carboxylate (8a-8j) has been developed by five steps which include activation of a methylene group, hydrazinolysis, cyclisation and chloro-amine coupling reactions. Moreover, our proposed mechanism was confirmed in this study demonstrating that ethyl 5-amino-1-(6-chloropyrimidin-4-yl)-1H-pyrazole-4-carboxylate is the key intermediate to fulfill the desired outcomes. In silico and in vitro studies were carried out to identify the active agents among the developed adducts against mycobacterium tuberculosis (PDB ID:4TRO). Compound 8a (Docking Score: -26.81 and MIC: 1.6 ug/mL) was found to be the most potent among the synthesized molecules. All the synthesized compounds showed acceptable drug-like properties which make them suitable for further lead modification using in silico design approaches.

Graphical abstract, The clinical manifestation of the recent pandemic COVID-19, caused by the novel SARS-CoV-2 virus, varies from mild to severe respiratory illness. Although environmental, demographic and co-morbidity factors have an impact on the severity of the disease, contribution of the mutations in each of the viral genes towards the degree of severity needs a deeper understanding for designing a better therapeutic approach against COVID-19. Open Reading Frame-3a (ORF3a) protein has been found to be mutated at several positions. In this work, we have studied the effect of one of the most frequently occurring mutants, D155Y of ORF3a protein, found in Indian COVID-19 patients. Using computational simulations we demonstrated that the substitution at 155th changed the amino acids involved in salt bridge formation, hydrogen-bond occupancy, interactome clusters, and the stability of the protein compared with the other substitutions found in Indian patients. Protein–protein docking using HADDOCK analysis revealed that substitution D155Y weakened the binding affinity of ORF3a with caveolin-1 compared with the other substitutions, suggesting its importance in the overall stability of ORF3a-caveolin-1 complex, which may modulate the virulence property of SARS-CoV-2.

Bioactive properties of piperazine derivatives are well known for its biological applications. In general, synthesis of bioactive compound is laborious and time consuming process. In the present investigation, the Microwave was used to synthesise two imines compounds using piperazine and various aldehydes in a quantitative yield. IR, NMR, UV, and elemental analysis techniques were used to characterise the compound 2a and 3a. In vitro method and docking experiments were used to investigate biological activities novel piperazines compounds. The antimicrobial activity of the synthesised compounds showed better results against Pseudomonas aeruginosa, with a MIC of 11.9 µg/ml. The antioxidant properties of the synthesised compounds were found to be high with the compound 2a has the smallest LC50 value (15 µg/ml). In silico docking of the BRCA1 protein in breast cancer cells confirmed an excellent binding affinity value of −7.10 kcal/mol. The findings of the anticancer analysis on the MDA MB-231 breast cancer cell line indicate that the drug-treated cells have a uniform structure with few abnormalities. Therefore, the synthesised compounds can be used in different biological applications.

An easy ZnO-TiS2 synthesis is described by a room temperature co-precipitation method. EDX, SEM, TEM methods were the main characteristics of the prepared nanocatalyst. For easy, efficient and green hydrazone, derivatives (5a-c) synthesis under the reflux temperature conditions, several factors such as the effect of molar ratios, catalyst loading, reaction time and the effect of solvent were investigated. The influence of catalyst loading on reactivity was studied, which resulted in an optimum catalyst load of 12 mol percent, giving the best return with a minimum of time compared with other catalysts. In this report, a fast and cost -effective synthesis of nanocatalysts and its diverse uses for hydrazone derivatives synthesis is reported. The analytical and spectral data of the synthesized hydrazone compounds have been characterized. The in vitro anti - inflammatory activities have been examined with the HRBC method for all the synthesized compounds. The anti - inflammatory activity was high in all compounds; compound 5a, in particular, produced a better effect, i.e. an IC50 value 165.7 similar to regular diclofenac. All the synthesized hydrazone derivatives were also studied through docking analysis for their interactions with COX-I enzymes. The binding affinities of each compound with the enzyme were good for the maximum value of −10 kcal/mol for 5c against COX-I.

Inhibition of the dihydroorotate dehydrogenase (DHODH) has been successful at the preclinical level in controlling myeloid leukemia. However, poor clinical trials warrant the search for new potent DHODH inhibitors. Herein we present a novel DHODH inhibitor SBL-105 effective against myeloid leukemia. Chemical characteristics were identified by 1H NMR, 13C NMR, and mass spectroscopy. Virtual docking and molecular dynamic simulation analysis were performed using the automated protocol with AutoDock-VINA, GROMACS program. Human-recombinant (rh) DHODH was used for enzyme inhibition study. THP-1, TF-1, HL-60, and SKM-1 cell lines were used. MTT assay was used to assess cell viability. Flow cytometry was employed for cell cycle, apoptosis, and differentiation analysis. Chemical analysis identified the compound to be 3-benzylidene-6,7-benz-chroman-4-one (SBL-105). The compound showed high binding efficacy toward DHODH with a Gbinding score of 10.9 kcal/mol. Trajectory analysis indicated conserved interactions of SBL-105DHODH to be stable throughout the 200-ns simulation. SBL-105 inhibited rh DHODH with an IC50 value of 48.48 nM. The GI50 values of SBL-105 in controlling THP-1, TF-1, HL-60, and SKM-1 cell proliferations were 60.66, 45.33, 73.98, and 86.01 nM, respectively. A dose-dependent increase in S-phase cell cycle arrest and total apoptosis was observed by SBL-105 treatment in both cell types, which were reversed in the presence of uridine. The compound also increased the differentiation marker CD11b-positive populations in both THP-1 and TF-1 cells, which were decreased under uridine influence. SBL-105, a novel DHODH inhibitor, identified using computational and in vitro analysis, was effective in controlling AML cells and needs attention for further preclinical developments.

Fungal glucans play a key role to provide energy, support cell structure, and present biological functions. However, the biosynthetic machineries of fungal glucan chains remain to be elucidated. Hence, we aimed to elucidate the biochemical and catalytic characteristics of a novel glucan synthesis-associated enzyme uridine diphosphate (UDP)-glycosyltransferase GFUGT88A1 derived from Grifola frondosa and predict its potential catalytic mechanism. The purified recombinant GFUGT88A1 had a molecular weight of 51.7 kDa with an optimum temperature of 37 °C and pH of 7.0. GFUGT88A1 showed preference for oligosaccharides with relatively higher polymerization degrees (≥6) as acceptors to extend its chain when using UDP-glucose as a donor. Molecular modeling and docking of GFUGT88A1 with donor UDP-glucose, and acceptors laminaribiose, laminarihexaose, and laminarinonaose indicated that the predicted amino acid residues at the active sites may bind the donor/acceptor protein primarily via hydrogen bonds with various binding energy values. The present study revealed that GFUGT88A1 extended glucan chains, which provides a reference to understand the biosynthesis pathway of mushroom glucans.

Numerous studies of medicinal and biological application of cucurbit[7]uril, CB[7] through host–guest formation intrigued to examine interaction of CB[7] host–guest complexes against various proteins. The complex formed between CB[7] and ferrocene derivatives are proved a stable one in solid state environment and supported such phenomenon in the theoretical calculations. However protein also had a strong interaction with CB[7] in many aspects that include bovine insulin and ubiquitin with CB[7] which confirms that protein interaction plays an important role in solution phase and gaseous phase and displayed exceptional binding stability. Thus the present work is focused to study the interaction of ternary system where Protein, CB[7] and N-(Ferrocenylmethyl) aniline (FMA) involved using In-Silico approach and the docking studies offered a different picture from the theoretical data so far obtained for the CB[7] – ferrocene derivatives.

RNA molecules play critical roles in cellular functions at the level of gene expression and regulation. The intricate 3D structures and the functional roles of RNAs make RNA molecules ideal targets for therapeutic drugs. The rational design of RNA-targeted drug requires accurate modeling of RNA-ligand interactions. Recently a new computational tool, RLDOCK, was developed to predict ligand binding sites and binding poses. Using an iterative multiscale sampling and search algorithm and a energy-based evaluation of ligand poses, the method enables efficient and accurate predictions for RNA-ligand interactions. Here we present a detailed illustration of the computational procedure for the practical implementation of the RLDOCK method. Using Flavin mononucleotide (FMN) docking to F. nucleatum FMN riboswitch as an example, we illustrate the computational protocol for RLDOCK-based prediction of RNA- ligand interactions. The RLDOCK software is freely accessible at http://https://github.com/Vfold-RNA/RLDOCK.

Background: Due to the prevalence of type-2 diabetes across the globe, there is unmet need to explore new molecular targets for the development of cost-effective and safer antihyperglycemic agents. Objective: Structural modification of phytol and evaluation of in vitro, in vivo and in silico antihyperglycemic activity of derivatives establishing the preliminary structure activity relationship (SAR). Methods: The semi-synthetic derivatives of phytol were prepared following previously described methods. The antihyperglycemic potential was measured in vitro in terms of increase in 2- deoxyglucose (2-DG) uptake by L-6 rat skeletal muscle cells as well as in vivo in sucrose-loaded (SLM) and streptozotocin (STZ)-induced diabetic rat models. The blood glucose profile was measured at 30, 60, 90, 120, 180, 240, 300 and 1440 min post administration of sucrose in rats. The in silico docking was performed on peroxisome proliferator-activated receptor gamma (PPARγ) as antidiabetic target along with absorption, distribution, metabolism, excretion and toxicity (ADMET) studies. Results: Nine semi-synthetic ester derivatives: acetyl (1), lauroyl (2), palmitoyl (3), pivaloyl (4), trans-crotonyl (5), benzoyl (6), m-anisoyl (7), 3,4,5-trimethoxy benzoyl (8) cinnamoyl (9) along with bromo derivative (10) of phytol were prepared. The derivatives 9, 8 and 2 caused 4.5, 3.2 and 2.7 times more in vitro uptake of 2-DG respectively than rosiglitazone (ROSI). The derivatives showed significant improvement in oral glucose tolerance both in SLM (29.6-21%) as well as STZ-induced diabetic (30.8-19.0%) rats. The in silico ADMET, docking studies showed non-toxicity and high binding affinity with PPARγ. Conclusion: The potent antihyperglycemic activity with favorable pharmacokinetics supports phytol derivatives as suitable antidiabetic lead.

Benzimidazole derivatives, especially 2-phenylbenzimidazole with various substituents on the C-5, C-2 and C-6 positions, are so important in pharmaceutical chemistry. Multiple linear regression was applied to predict the activity of 27 novel 2-phenylbenzimidazole derivatives as anticancer agents. At first, we made an effort to create a QSAR model for a selected series of novel 2-phenylbenzimidazole with density functional theory and molecular docking descriptors. Then, we tried to investigate the nature of the interactions between 2-phenylbenzimidazole derivatives and the estrogen receptor using the molecular docking method. Six descriptors of MATS4e, GATS5e, R6v, R1v+, dipole moment, and torsional free energy were selected for modelling. Due to docking results, increase in the binding energy, and decrease in the dipole moment could increase inhibitor activity.

We studied angiotensin I converting enzyme (ACE) inhibitory effect of the protein hydrolysates prepared from commercially available nori products that contain Pyropia pseudolinearis as the main ingredient. The water extract of the nori product consisted mainly of phycobiliproteins and RubisCO. The proteins in the aqueous extracts were sequentially hydrolyzed with pepsin and trypsin, and the peptides in the pepsin-trypsin digests were fractionated by reversed-phase HPLC. As a result, 12 ACE inhibitory peptides containing ten novel peptides were identified. These peptides are suggested to have originated from the alpha- and beta-subunits of phycobiliproteins and the large subunits of RubisCO of P. pseudolinearis. The interactions of eight peptides (ALR, FAR, FSR, FDR, EVYR, AYR, GRP, and MVT) with ACE were then simulated using the flexible docking tool Auto Dock Vina. The results showed that all peptides interacted with the active center of ACE, and their docking scores ranged from - 6.8 to - 10.2 kcal/mol. In addition, we synthesized four peptides (AYR, FAR, EVYR, and GRP) and measured the IC50 values of these peptides for ACE. Consequently, FAR and GRP showed considerably low IC50 values (0.29 mu mol and 0.45 mu mol, respectively) in addition to other ACE inhibitory peptides. Moreover, FAR, which is specific to the nori product, was predicted to bind to the S1, S1 ', and S2 ' subsites of the catalytic center of ACE. Therefore, it can be expected that daily intake of "nori products" may have a positive effect on the prevention of hypertension.

Background and purpose: Antiplatelet agents can diminish the chance of coronary heart diseases due to the prevention of unusual clotting in the arteries by inhibiting platelet aggregation and avoiding the formation of a blood clot. This mechanism can help to prevent ischemic stroke likewise. To improve the activity of these drugs and reduce their side effects, further studies are required. Experimental approach: Based on the previous studies representing the promising antiplatelet activity of indole hydrazones, a series of their homologs containing twenty-one compounds were prepared in two steps. First, alkylation reaction on the nitrogen of the indole ring, and second, chiff base formation by condensation of a primary amine and N-substituted indole-3 carbaldehyde. Consequently, their platelet anti-aggregation activity was evaluated based on the Born turbidimetric method. Findings/Results: Most of the compounds exhibited noticeable activity against platelet aggregation induced by arachidonic acid. Amongst them, two compounds 2e and 2f showed higher activity with IC50 values that made comparable to indomethacin and acetylsalicylic acid as standard drugs and had no toxicity on platelets. Conclusion and implications: The synthesized compounds exhibited promising activity against arachidonic acid-induced aggregation; however, none of them showed noticeable antiplatelet activity induced by adenosine di-phosphate. Chemical structure comparison of the prepared derivatives indicated the existence of a lipophilic medium-sized group on the phenyl ring increased their activity. In addition, the docking studies confirmed this hydrophobic interaction in the lipophilic pocket of cyclooxygenase-1 enzyme suggesting that hydrophobicity of this region plays a pivotal role in the anti-platelet activity of these compounds. To prove this finding, the enzymatic evaluation with the target enzyme is required.

A collection of solid-state emitters based on Oxazolone-Coumarin Triazoles with the potential to induce apoptosis in human cervical cancer cell line HeLa is reported. These new classes of fluorescent inhibitors were synthesized by the sequential use of multicomponent reactions (MCR) and click chemistry with oxazolone alkynes and coumarin azides and the origin of their solid state emission properties were related to an unconventional AIE process. The significantly high first-order hyperpolarizability values (36-118 times higher than the standard molecule urea) obtained from the DFT calculations showed that the emission from these molecules follows nonlinear optical characteristics. The molecules also showed excellent binding affinity towards CDK2 with high docking scores and the binding sites obtained from docking studies are in good agreement with the reactivity sites determined from the DFT-based Molecular electrostatic potential (MEP) analysis. Cytotoxicity studies of the selected molecules showed the potential of these molecules as inhibitors of human cervical cancer cells (HeLa). Overall, the optical and biological properties of these new solid-state emitters are promising for a broad spectrum of applications in medicinal and materials chemistry.

Background and purpose: In this study, some new cytotoxic hybrid structures were synthesized by combining pyrazolinone and imidazolinone rings with quinazoline pharmacophores. Experimental approach: The benzoxazinone, pyrazolo-quinazoline fused ring, and imidazolinone anchored quinazoline derivatives were synthesized by simple ring-opening, ring expansion, and ring closure strategies from oxazolones. The molecular docking studies of the final derivatives were accomplished on the epidermal growth factor receptor enzyme. The cytotoxic effect of the final compounds on the MCF-7 cell line was evaluated by MTT assay. Findings/Results: The docking results confirmed the optimized electrostatic, H-bonding, and hydrophobic interactions of structures with the key residues of the active site (DG bin < -9Kcal/mol). The derivatives have been obtained in good yield and purity, and their structures were confirmed by different methods (FT-IR, 1 H-NMR, 13 C-NMR, and CHNS analysis). The IC50s of all final derivatives against the MCF-7 cell line were lower than 10 μM, and between all, the IXa from pyrazolo-quinazolinone class (IC 50 : 6.43 µM) with chlorine substitute was the most potent. Furthermore, all derivatives showed negligible cytotoxicity on HUVEC normal cell line which would be a great achievement for a novel cytotoxic agent. Conclusion and implications: Based on the obtained results, pyrazolo[1,5-c] quinazolin-2-one series were more cytotoxic than imidazolinone methyl quinazoline-4(3H)-ones against MCF-7 cells. Chlorine substitute in the para position of the aromatic ring improved the cytotoxicity effect in both classes. It could be related to the polarizability of a chlorine atom and making better intermolecular interactions. Further pre-clinical evaluations are required for the promising synthesized cytotoxic compounds.

Twist1 promote the bypass of p53 response by interacting with p53 and facilitating its MDM2-mediated degradation. We reasoned that reagents able to interfere with the p53:Twist1 complex might alleviate Twist1 inhibitory effect over p53, thus representing potential therapeutic tools in p53 wild type tumors. From a pre-immune library of llama nanobodies (VHH), we isolated binders targeting the p53 C-terminal region (p53-CTD) involved in the interaction with Twist1 by using recombinant Twist1 as an epitope-specific competitor during elution. Positive hits were validated by proving their capacity to immunoprecipitate p53 and to inhibit Twist1:p53 binding in vitro. Molecular modeling confirmed a preferential docking of positive hits with p53-CTD. D11 VHH activity was validated in human cell models, succeeded in immunoprecipitating endogenous p53 and, similarly to Twist1 knock-down, interfered with p53 turnover, p53 phosphorylation at Serine 392 and affected cell viability. Despite the limited functional effect determined by D11 expression in target cells, our results provide the proof of principle that nanobodies ectopically expressed within a cell, have the capacity to target the assembly of the pro-tumorigenic Twist1:p53 complex. These results disclose novel tools for dissecting p53 biology and lay down the grounds for the development of innovative targeted therapeutic approaches.

This paper describes the spectroscopic (FT-IR and UV–Visible), electronic, structural, vibrational properties of celecoxib compound using density functional theory. The optimized geometry structure of the titled molecule is explained by the method of B3LYP with 6–31 + G (d, p) basis set. We found that the simulated optimized geometry of the titled molecule is simulated to the experimental ones. The infrared spectrum of celecoxib compound is represented in the present work. The computational information about the organic molecule can be explained by the charge transfer properties, which is a computational tool for the precise quantum chemical calculations of space charge density distribution and HOMO-LUMO states. The transition states of celecoxib compound have explained by the time-dependent density functional theory (TD-DFT) which is observed by the UV–visible spectrum. Docking research [1] is a modeling method, with the help of docking method we can find out new drug and chemical behavior of the drug which is useful in the application purpose of the drug, the interaction between protein and legends provides the information of the binding energy and physical parameter like partition function, free energy, internal energy, entropy.

The molecule ((E)-1-(2-hydroxy-5-nitrobenzylidene)semicarbazide was synthesized and vibrational spectroscopic investigations have been performed by DFT which is very efficient tool for structural elucidation of bioactive molecules. The experimental and theoretical FT-IR and FT-Raman spectra have been reported together with the assignments of the vibrational modes that supported by PED. HOMO-LUMO analysis has been performed to elucidate charge transfer occurring in the molecule and compared with UV–Vis data. In addition, 2H5NS has been screened for antibacterial process for Gram positive bacteria, Gram negative bacteria and antifungal at two different concentrations of 100 and 200 μg/ml. Docking analysis has been performed to find out the binding affinity and drug activity of the molecule.

With the development of structural biology and data mining, computer-aided drug design (CADD) has been playing an important role in all aspects of new drug development. Reverse docking, a method of virtual screening based on molecular docking in CADD, is widely used in drug repositioning, drug rescue, and traditional Chinese medicine (TCM) research, for it can search for macromolecular targets that can bind to a given ligand molecule. This review revealed the principle of reverse docking, summarized common target protein databases and docking procedures, and enumerated the applications of reverse docking in drug repositioning, adverse drug reactions, traditional Chinese medicine, and coronavirus disease 2019 (COVID-19) treatment. Hope our work can give some inspiration to researchers engaged in drug development.

The present methodology offers a domino reaction strategy, high yield, simpler operation, recyclable and environmentally friendly. A number of [E]-N benzylidene-3,5-dichloropyridine-4-amines were synthesized from 3,5-dichloropyridine-4-amine and aromatic aldehydes with 5 mol% of nanocatalyst. IR and NMR spectroscopic techniques characterized structures of all synthesized compounds. The antimicrobial activities were screened for all synthesized [E]–N‐benzylidene-3,5-dichloropyridine-4-amines. Docking studies with DNA Gyrase receptor have been conducted. Comparison of Docking scores with standard ciprofloxacin medicinal products. Most of the synthesized compounds have been well suited to all the docked targets at the working site.

The quantitative structure–activity relationship (QSAR) with anticancer activity approach was performed on a series of azacalix [2] arene [2] pyrimidines derivatives. The multiple linear regressions (MLR) and multiple non linear regressions (MNLR) were used to generate the linear and the non-linear 2d-QSAR models, based on the calculated descriptors by the density functional theory DFT (B3LYP/6-31G) performed with GaussView, chemsketch and chemoffice software. The selected model was tested by the internal validation, Y-randomization, and external validation. Besides 2D-QSAR technique, molecular docking analysis show that the compound chooses for the docking has a good affinity towards the protein kinase CK2. The results of QSAR, and molecular docking studies could help scientists to propose novel compounds with higher anti-cancer activities. Therefore, they could reduce time, cost and even the availability of the laboratories equipped to carry out the synthesizers and tests.

Organic anion transporters (OATs) belong to a subgroup of the solute carrier 22 transporter family. OATs have a central role in xenobiotic disposition affecting the toxicokinetics of its substrates and inter-individual differences in their expression, activity and function impact both toxicokinetics and toxicodynamics. Amongst OATs, OAT1 (solute carrier family 22 member 6) is involved in the urinary excretion of many xenobiotics bringing substrates into renal proximal tubular cells which can then be secreted across the apical membrane into the tubule lumen. The mycotoxin ochratoxin A has been shown to have a high affinity for OAT1, which is an important renal transporter involved in its urinary excretion. Nowadays, molecular modeling techniques are widely applied to assess protein-ligand interactions and may provide a tool to depict the mechanistic of xenobiotic action be it toxicokinetics or toxicodynamics. This work provides a structured pipeline consisting of docking and molecular dynamic simulations to study OAT1-ligand interactions and the impact of OAT1 polymorphisms on such interactions. Such a computational structure-based analytical framework allowed to: i) model OAT1-substrate complex formation and depict the features correlating its sequence, structure and its capability to recruit substrates; and ii) investigate the impact of OAT1 missense mutations on substrate recruitment. Perspectives on applying such a structured pipeline to xenobiotic-metabolising enzymes are discussed.

Novel bioactive piperazine derivatives are synthesised and charecterised by IR, NMR, UV, and elemental analysis techniques. The biological activity of the synthesised materials is investigated by using In vitro and docking experiments. The novel imines were prepared in quantitative yield using the microwave technique. The compound 2a and 3a are charecterised IR, NMR, UV, and elemental analysis techniques and confirm the formation of the desired product. The antimicrobial activity of the synthesised compounds showed excellent activity with compound 2a and 3a having the highest activity of about 6 µg/ml against Enterococcus Faecalis and Pseudomonas aeruginosa, respectively. The antioxidant properties of the synthesised compounds were investigated and the compound 2a has the smallest LC50 value (9 µg/ml). In silico docking of the BRCA1 protein in breast cancer cells confirmed an excellent binding affinity value of −7.10 kcal/mol. Similarly, invitro anticancer analysis on the MDA MB-231 breast cancer cell line indicate that the drug-treated cells have a uniform structure with few abnormalities.

Glutathione S-transferase P1 (GSTP1) is a promising target for cancer prevention and therapy, particularly because of its involvement in promoting cancer cell survival and resistance of tumors to therapeutic agents. In fact, multiple GSTP1 antagonists have been developed for cancer treatment; however, none of these inhibitors have been successfully used in clinical applications, probably because of the extreme complexity and high risk of translating molecules of novel drug discovery to clinical use. To overcome this obstacle, the strategy of drug repurposing was used in this study to identify potential GSTP1 inhibitors via structure-based virtual screening of compounds in the FDA database. Following this, fosaprepitant was identified as a potential GSTP1 inhibitor through a thorough assessment of docking scores, as well as interaction modes for further verification. Molecular docking and molecular dynamics simulations were performed to obtain a complex structure between the relatively stable inhibitor, fosaprepitant and GSTP1. Furthermore, based on the results of the microscale thermophoresis (MST) assay, fosaprepitant displayed good binding affinity with a Kd value of 62.5±5.8 nM. Inhibitory assays showed that fosaprepitant was a potent inhibitor of GSTP1 with an average IC50 value of 278.7±21.1 nM. Of note, fosaprepitant exhibited superior toxicity towards A549/DDP cells that overexpressed GSTP1 compared with the A549 cell line, which further supported its potential use as an effective GSTP1 inhibitor. In addition, the molecule showed significant ability to induce cell apoptosis in the A549/DDP cell line. Overall, these results provide new insights into the biological functions of specific small molecule inhibitors of GSTP1.