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Targeting epigenetics is a new strategy to treat cancer and develop novel epigenetic drugs with anti-tumor activity. DNA methyltransferases transfer the methyl group from S-adenosyl-L-methionine (SAM) to the cytosine residue in a CpG island, leading to the transcription silencing of the gene. Hypermethylation can frequently be observed in several tumor types. Hence, the inhibition of DNMT1 has become a novel approach to cure cancer. In this study, virtual screening and molecular docking were performed for more than 11,000 ligands from the ZINC15 database to discover new hypomethylation agents. Four candidate compounds were further tested for their effects on DNMT1 in silico and in vitro. Compounds 2 and 4 showed the best DNMT1 inhibitory activity, but only compound 4 was able to inhibit the growth of several cancer cell lines. The hypomethylation of the luciferase gene by compound 4 was verified by a CMV- luciferase assay using KG-1 cells. Additionally, compound 4 suppressed cell migration in a dose- and time-dependent manner in the wound healing assay. Moreover, cell cycle analyses demonstrated that compound 4 arrested CCRF-CEM cells and MDA-MB-468 cells in the G0/G1 phase. Also, compound 4 significantly induced early and late apoptosis in a dose-dependent manner. In conclusion, we introduce compound 4 as a novel DNMT1 inhibitor with anticancer activity. [ABSTRACT FROM AUTHOR]

Bacterial infections are evolving and one of the chief problems is emergence and prevalence of antibacterial resistance. Moreover, certain strains of Bacillus subtilis have become resistant to several antibiotics. To counteract this menace, the present work aimed to comprehend the antibacterial activity of synthesized two quinoline derivatives against Bacillus subtilis. Toxicity predictions via Protox II, SwissADME and T.E.S.T (Toxicity Estimation Software Tool) revealed that these derivatives were non-toxic and had little to no adverse effects. Molecular docking studies carried out in Schrodinger with two quinoline derivatives (referred Q1 and Q2) docked against selected target proteins (PDB IDs: 2VAM and1FSE) of B. subtilis demonstrated ideal binding energies (2VAM-Q1: − 4.63 kcal/mol and 2VAM-Q2: − 4.46 kcal/mol, and 1FSE-Q1: − 3.51 kcal/mol, 1FSE-Q2: − 6.34 kcal/mol). These complexes were simulated at 100 ns and the outcomes revealed their stability with slight conformational changes. Anti-microbial assay via disc diffusion method revealed zones of inhibition showing that B. subtilis was inhibited by both Q1 and Q2, with Q2 performing slightly better than Q1, pointing towards its effectiveness against this organism and necessitating further study on other bacteria in prospective studies. Thus, this study demonstrates that our novel quinoline derivatives exhibit antibacterial properties against Bacillus subtilis and can act as potent anti-bacterials. [ABSTRACT FROM AUTHOR]

The research aims to elucidate how drug interactions affect the activity of L‐asparaginase (L‐ASNase), an essential enzyme in cancer treatment, especially for acute lymphoblastic leukemia (ALL). Understanding these interactions is crucial for optimizing treatment effectiveness and reducing adverse effects. This study explores the intricate molecular interactions and structural dynamics of L‐ASNase upon binding with colchicine. Fluorescence quenching experiments were conducted at various temperatures (298, 303, and 310 K), revealing notable interactions between L‐ASNase and colchicine. These interactions were characterized by a reduction in fluorescence intensity and a blue shift in emission maxima. Additional analyses, including the determination of Stern–Volmer quenching constants (KSV), bimolecular quenching rate constants (kq), and thermodynamic parameters, indicated a static quenching mechanism with moderate binding affinities (Ka: 1.40–2.71 × 104 M−1) across different temperatures. Thermodynamic study suggested positive enthalpy and entropy changes (ΔH° = −10.26 kcal mol−1; ΔS° = −14.19 cal mol−1 K−1), suggesting a spontaneous reaction with negative ΔG° values (−5.86 to −6.03 kcal mol−1). FRET measurements supported optimal distances (r and Ro) for FRET occurrence, reinforcing the static quenching mechanism. Molecular docking further supported these findings, revealing a 1:1 stoichiometric binding ratio for L‐ASNase:colchicine and elucidating specific binding orientations and interactions critical for complex stability. Subsequent molecular dynamics simulations spanning 100 ns underscored the stability of the L‐ASNase–colchicine complex, with minimal deviations observed in key structural parameters such as RMSD, RMSF, Rg, and SASA. Additionally, spectroscopic analyses, including circular dichroism (CD), synchronous fluorescence, and 3D fluorescence provided insights into the conformational changes and alterations in the microenvironment of aromatic amino acid residues in L‐ASNase upon colchicine binding. Moreover, L‐ASNase activity was slightly reduced by 25% in the presence of colchicine. This comprehensive investigation sheds light on the molecular intricacies of the L‐ASNase–colchicine complex, advancing our understanding of drug–target interactions and offering potential avenues for therapeutic applications. [ABSTRACT FROM AUTHOR]

Background: Hyperlipidemia is a common precursor to cardiovascular diseases, necessitating effective intervention. This study explores the potential of a bioactive fraction derived from Kalanchoe pinnata leaf, a less-explored natural source, for its antihyperlipidemic properties. Objectives: The primary objectives of this research are to isolate and assess the bioactive fraction from Kalanchoe pinnata leaves extract for its antihyperlipidemic attributes using a murine model. The study also aims to characterize the fraction and investigate its interactions with hyperlipidemia-related proteins. Materials and Methods: Kalanchoe pinnata leaves were extracted and fractionated via flash chromatography. Isolated fractions underwent phytochemical, antioxidant, and enzyme inhibition assays in vitro. In vivo, selected fractions were tested in Triton WR-1339-induced hyperlipidemic mice. Fraction F2, which exhibits the most potent activity, was characterized using HPTLC MS/MSn chromatography. Molecular docking studies explored interactions between F2 compounds and hyperlipidemia-related proteins. Results: Fraction F2 displayed significant in vivo antihyperlipidemic activity, with observable morphological changes in mice. HPTLC MS/MSn identified four major compounds in F2, while docking studies revealed potential interactions with hyperlipidemia-related proteins. Conclusion: This study underscores F2's potential as a potent antihyperlipidemic agent sourced from Kalanchoe pinnata leaves. The identified compounds hold promise for further research in hyperlipidemia therapy development, emphasizing the therapeutic potential of natural Kalanchoe pinnata compounds for managing hyperlipidemia and related cardiovascular conditions. [ABSTRACT FROM AUTHOR]

Lactoferrin (LF), a multifunctional glycoprotein found in mammalian milk and various exocrine secretions, plays a pivotal role in modulating various responses. Lactoferrin plays a significant role in type-2 diabetes by improving hepatic insulin resistance and pancreatic dysfunction however, the exact mechanism for this improvement is not thoroughly elucidated. To this date, there are no evidence that attributes the direct interaction of lactoferrin with components of NF-κB pathway. Considering this precedent, the current study aimed to investigate the interaction of LF with key components of NF-κB pathway using molecular docking and simulation approaches. Results indicated that LF has shown highly stable interactions with IL-1β, IL-6, IκBα and NF-κB, and relatively weaker interactions with IKK and TNF-α. All four trajectories, including root mean square of deviations (RMSD), root mean square of fluctuation (RMSF), hydrogen bond interactions, and radius of gyration (RoG), confirmed the stable interactions of LF with NF-κB pathway components. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) analysis further supports their stable interactions. To the best of our knowledge, this is the first study to provide convincing evidence that LF can interact with all six major components of the NF-κB pathway. This study provides pioneering in-silico evidence that lactoferrin (LF) can interact with all six major components of the NF-κB pathway, demonstrating highly stable interactions with IL-1β, IL-6, IκBα, and NF-κB, and relatively weaker interactions with IKK and TNF-α. These findings suggest that LF and its peptides have significant potential for both preventive and therapeutic applications by targeting the NF-κB pathway to inhibit inflammation, thereby improving insulin sensitivity and aiding in the management of diabetes.

Introduction: The emergence of a new and highly pathogenic coronavirus (SARS-CoV-2) in Wuhan (China) and its spread worldwide has resulted in enormous social and economic losses. Amongst many proteins encoded by the SARS-CoV-2 genome, the main protease (Mpro) or chymotrypsin-like cysteine protease (3CLpro) and papain-like protease (PLpro) serve as attractive drug targets. Material and methods: We screened a library of 2267 natural compounds against Mpro and PLpro using high throughput virtual screening (HTVS). Fifty top-scoring compounds against each protein in HTVS were further evaluated by standard-precision (SP) docking. Compounds with SP docking energy of ≤ -8.0 kcal/mol against Mpro and ≤ -5.0 kcal/mol against PLpro were subjected to extra-precision (XP) docking. Finally, six compounds against each target proteins were identified and subjected to Prime/MM-GBSA free energy calculations. Compounds with the lowest Prime/MM-GBSA energy were subjected to molecular dynamics simulation to evaluate the stability of protein-ligand complexes. Results: Proanthocyanidin and rhapontin were identified as the most potent inhibitors of Mpro and PLpro, respectively. Analysis of protein-inhibitor interaction revealed that both protein-inhibitor complexes were stabilized by hydrogen bonding and hydrophobic interactions. Proanthocyanidin interacted with the catalytic residues (His41 and Cys145) of Mpro, while rhapontin contacted the active site residues (Trp106, His272, Asp286) of PLpro. The docking energies of proanthocyanidin and rhapontin towards their respective targets were -10.566 and -10.022 kcal/mol. Conclusions: This study's outcome may support application of proanthocyanidin and rhapontin as a scaffold to build more potent inhibitors with desirable drug-like properties. However, it requires further validation by in vitro and in vivo studies. [ABSTRACT FROM AUTHOR]

Glioma coined as a "butterfly" tumor associated with a dismal prognosis. Marine algal compounds with the richest sources of bioactive components act as significant anti-tumor therapeutics. However, there is a paucity of studies conducted on Fucoidan to enhance the anti-glioma efficacy of Temozolomide. Therefore, the present study aimed to evaluate the synergistic anti-proliferative, anti-inflammatory and pro-apoptotic effects of Fucoidan with Temozolomide in in vitro and in silico experimental setup. The anti-proliferative effects of Temozolomide and Fucoidan were evaluated on C6 glioma cells by MTT and migration assay. Modulation of inflammatory markers and apoptosis induction was affirmed at the morphological and transcriptional level by dual staining and gene expression. Molecular docking (MD) and molecular dynamics simulation (MDS) studies were performed against the targets to rationalize the inhibitory effect. The dual-drug combination significantly reduced the cell viability and migration of glioma cells in a synergistic dose-dependent manner. At the molecular level, the dual-drug combination significantly down-regulated inflammatory genes with a concomitant upregulation of pro-apoptotic marker. In consensus with our in vitro findings, molecular docking and simulation studies revealed that the anti-tumor ligands: Temozolomide, Fucoidan with 5-(3-Methy1-trizeno)-imidazole-4-carboxamide (MTIC), and 4-amino-5-imidazole-carboxamide (AIC) had the potency to bind to the inflammatory proteins at their active sites, mediated by H-bonds and other non-covalent interactions. The dual-drug combinatorial treatment synergistically inhibited the proliferation, migration of glioma cells and promoted apoptosis; conversely with the down-regulation of inflammatory genes. However, pre-clinical experimental evidence is warranted for the possible translation of this combination. [ABSTRACT FROM AUTHOR]

The binding affinity of a drug with carrier proteins plays a major role in the distribution and administration of the drug within the body. Tizanidine (TND) is a muscle relaxant having antispasmodic and antispastic effects. Herein, we have studied the effect of tizanidine on serum albumins by spectroscopic techniques, such as absorption spectroscopic analysis, steady, state fluorescence, synchronous fluorescence, circular dichroism, and molecular docking. The binding constant and number of binding sites of TND with serum proteins were determined by means of fluorescence data. The thermodynamic parameters, like Gibbs' free energy (ΔG), enthalpy change (ΔH), and entropy change (ΔS), revealed that the complex formation is spontaneous, exothermic, and entropy driven. Further, synchronous spectroscopy revealed the involvement of Trp (amino acid) responsible for quenching of intensity in fluorescence in serum albumins in presence of TND. Circular dichroism results suggest that more folded secondary structure of proteins. In BSA the presence of 20 μM concentration of TND was able to gain most of its helical content. Similarly, in HSA the presence of 40 μM concentration of TND has been able to gain more helical content. Molecular docking and molecular dynamic simulation further confirm the binding of TND with serum albumins, thus validating our experimental results. [ABSTRACT FROM AUTHOR]

Background: Antibiotic resistance in bacteria mediated by New Delhi Metallo-β-lactamase (NDM) is a global threat to human health with an enormous economic burden. NDM can hydrolyze all the β-lactam core-containing antibiotics including carbapenems, which are regarded as last resort antibiotics. Materials and Methods: A library of Abyssomicins was virtually screened to identify novel non-β-lactam ring-containing inhibitors of NDM-1. Different computational approaches such as molecular modeling, virtual screening, molecular docking, molecular dynamics simulation, ADMET profiling, and free energy calculations were utilized for this purpose. Results: Virtual screening and ADMET profiling shortlisted Abyssomicin W and Neoabyssomicin B as the most promising candidate molecules. An in-depth analysis of protein-ligand interactions by molecular docking revealed that both ligands bind the active site of NDM-1. The identified inhibitors interacted with key catalytic residues as well as other residues around the active site of NDM-1. Hydrogen bonding and hydrophobic interactions played a significant role in stabilizing the protein-inhibitor complexes. The docking energy of NDM-1-Abyssomicin W, and NDM-1-Neoabyssomicin B complexes were − 9.6 kcal/mol and − 9.5 kcal/mol, respectively, which were higher than NDM-1-Methicillin (control) complex (−7.3 kcal/mol). Molecular dynamics simulation and free energy calculations by MM-PBSA also confirmed the stability of NDM-1-Abyssomicin W, and NDM-1-Neoabyssomicin B complexes. Conclusion: The findings of this study suggest that Abyssomicins serve as potential inhibitors of NDM-1. However, these results need to be validated in vitro and in vivo. This study may serve as a basis for further developing Abyssomicins as novel inhibitors of β-lactamases. [ABSTRACT FROM AUTHOR]

The research aims to elucidate how drug interactions affect the activity of L-asparaginase (L-ASNase), an essential enzyme in cancer treatment, especially for acute lymphoblastic leukemia (ALL). Understanding these interactions is crucial for optimizing treatment effectiveness and reducing adverse effects. This study explores the intricate molecular interactions and structural dynamics of L-ASNase upon binding with colchicine. Fluorescence quenching experiments were conducted at various temperatures (298, 303, and 310 K), revealing notable interactions between L-ASNase and colchicine. These interactions were characterized by a reduction in fluorescence intensity and a blue shift in emission maxima. Additional analyses, including the determination of Stern-Volmer quenching constants (K SV ), bimolecular quenching rate constants (k q ), and thermodynamic parameters, indicated a static quenching mechanism with moderate binding affinities (K a : 1.40-2.71 × 10 4  M -1 ) across different temperatures. Thermodynamic study suggested positive enthalpy and entropy changes (ΔH° = -10.26 kcal mol -1 ; ΔS° = -14.19 cal mol -1  K -1 ), suggesting a spontaneous reaction with negative ΔG° values (-5.86 to -6.03 kcal mol -1 ). FRET measurements supported optimal distances (r and R o ) for FRET occurrence, reinforcing the static quenching mechanism. Molecular docking further supported these findings, revealing a 1:1 stoichiometric binding ratio for L-ASNase:colchicine and elucidating specific binding orientations and interactions critical for complex stability. Subsequent molecular dynamics simulations spanning 100 ns underscored the stability of the L-ASNase-colchicine complex, with minimal deviations observed in key structural parameters such as RMSD, RMSF, R g , and SASA. Additionally, spectroscopic analyses, including circular dichroism (CD), synchronous fluorescence, and 3D fluorescence provided insights into the conformational changes and alterations in the microenvironment of aromatic amino acid residues in L-ASNase upon colchicine binding. Moreover, L-ASNase activity was slightly reduced by 25% in the presence of colchicine. This comprehensive investigation sheds light on the molecular intricacies of the L-ASNase-colchicine complex, advancing our understanding of drug-target interactions and offering potential avenues for therapeutic applications., (© 2024 John Wiley & Sons Ltd.)

• Silibinin induced conformational changes in β-lactoglobulin. • Both Secondary and tertiary structure of β-lactoglobulin was perturbed by silibinin. • Strong binding affinities (Ka range: 0.138–1.483 × 105 M−1) between BLG-Silibinin complex was observed. • The β-LG and Silibinin complex is primarily stabilized by hydrogen bonds and hydrophobic interactions. • Antioxidant capacity of β-LG increased after complexation with silibinin. This study investigates the comprehensive characterization of the interaction between β-lactoglobulin (β-LG) and Silibinin using various spectroscopic techniques. Fluorescence quenching experiments at different temperatures (298, 303, 308, and 313 K) revealed substantive interactions between β-LG and Silibinin, as indicated by a reduction in fluorescence intensity and a red shift in emission maxima. Further analysis, including Stern-Volmer quenching constants (K SV), bimolecular quenching rate constants (k q), and thermodynamic parameters demonstrated static quenching mechanism and strong binding affinities (K a range: 0.138–1.483 × 105 M−1) between BLG-Silibinin complex. Thermodynamic study suggested positive enthalpy and entropy changes (Δ Ho =43.31 kcal mol−1; Δ So =164.33 cal mol−1 K−1), suggesting a spontaneous reaction with negative Δ Go values (-5.66 to -7.30 kcal mol−1). Forster resonance energy transfer (FRET) measurements confirmed optimal distances (r and R o) for FRET occurrence, endorsing the static quenching mechanism. Molecular docking supported these findings, showcasing a 1:1 stoichiometric binding ratio for β-LG: Silibinin. The β-LG and Silibinin complex is primarily stabilized by hydrogen bonds and hydrophobic interactions. Molecular dynamics simulations over 200 ns highlighted stability in the β-LG-Silibinin complex, indicated by RMSD convergence, consistent RMSF values, and compactness illustrated by Rg. Conformational changes in β-LG upon Silibinin binding were further confirmed through UV-Vis absorption spectroscopy, FTIR, far-UV CD, synchronous fluorescence, and 3D fluorescence analyses. Functionally, the antioxidant capacity of β-LG increased after complexation with silibinin as quantified by DPPH assay. These results collectively depict the intricate network of interactions between Silibinin and β-LG, shedding light on the molecular details of their binding and offering insights into potential functional implications in biological contexts. [ABSTRACT FROM AUTHOR]

Intestinal immunity plays a pivotal role in overall immunological defenses, constructing mechanisms against pathogens while maintaining balance with commensal microbial communities. Existing therapeutic interventions may lead to drug resistance and potential toxicity when immune capacity is compromised. Dendrobium officinale , a traditional Chinese medicine, contains components identified to bolster immunity. Employing network pharmacology strategies, this study identified constituents of Dendrobium officinale and their action targets in the TCMSP and Swiss Target Prediction databases, and compared them with intestinal immunity-related targets. Protein-protein interaction networks revealed the core targets of Dendrobium officinale polysaccharides, encompassing key pathways such as cell proliferation, inflammatory response, and immune reactions, particularly in association with the Toll-like receptor 4. Molecular docking and molecular dynamics simulation further confirmed the high affinity and stability between Dendrobium officinale polysaccharides and Toll-like receptor 4. In vivo experiments demonstrated that Dendrobium officinale polysaccharides modulates the expression of Toll-like receptor 4 and its downstream key proteins in the colonic mucosa of mice. Consequently, these findings suggest that Dendrobium officinale polysaccharides may serve as a potential modulator for intestinal immune functions, with its mechanism potentially related to the Toll-like receptor 4. [Display omitted] • DOP Revealed as Intestinal Immunomodulator via Network Pharmacology. • TLR4: Key Target for DOP with High Affinity, Confirmed by Docking. • Molecular Docking Validates DOP's Role in Intestinal Immunity. • Animal Studies Show DOP Modulates TLR4, Backing Therapeutic Potential. [ABSTRACT FROM AUTHOR]

• A novel series of 1,2,3-triazole based 1,3,4-thiadiazole derivatives were designed, synthesized and evaluated for their cytotoxic activity. • Anti-proliferative activity was assessed against HT-1080, A-549, MCF-7 and MDA-MB-231 cells lines. • Hybrid compound 14a showed important inhibitory activity against MCF-7 and MDA-MB-231 cells lines. • Binding modes of all compounds were identified via molecular docking. • Compounds had higher affinity for Bcl-XL as compared to other compounds. One sets of 1,3,4-thiadiazole analogs 14a-c and 15a-c were synthesized by the incorporation of two heterocyclic nuclei (1,2,3-triazole & 1,3,4-thiadiazoles) in objective of developing multifunctional molecules for anticancer disease. (R)-Carvone was used as precursors for the synthesis of new heterocycles. The 1,2,3-triazole-1,3,4-thiadiazoles 14a-c and 15a-c were synthesized in good yields from the precursors using simple procedures. The chemical structures of all the newly synthesized hybrids were established using (1H and 13C) NMR and HRMS analysis. The in vitro assessment of the activity of the resultant 1,2,3-triazole-1,3,4-thiadiazoles against human cancer cells, namely fibrosarcoma (HT-1080), lung carcinoma (A-549) and breast carcinoma (MCF-7 and MDA-MB-231) was performed using viability testing (MTT). Compound 14a was the most active heterocycle, and its cytotoxic activity was three times less actives comparable to that obtained for Doxorubicin (6 µM) as a reference. The 1,3,4-thiadiazoles 15a-c showed moderate cytotoxic activities with IC 50 values ranging from 25.56 ± 1.13 to 61.81 ± 2.21 μM. Molecular docking studies were conducted against two antiapoptotic proteins namely Bcl-2, and Bcl-XL to elucidate the potential mechanisms of action. The results indicate that compounds interact favorably (binding energy = −7.6 to −9.8 kcal/mol) with the target proteins through hydrophobic, electrostatic interactions, and hydrogen bonding. The negative binding energy indicate the spontaneous nature of the interaction. Further, molecular dynamics simulation parameters such as root mean square deviation, root mean square fluctuation, radius of gyration, and solvent accessible surface area provided insights into the stability and dynamics of the protein-ligand complexes. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction The emergence of a new and highly pathogenic coronavirus (SARS-CoV-2) in Wuhan (China) and its spread worldwide has resulted in enormous social and economic losses. Amongst many proteins encoded by the SARS-CoV-2 genome, the main protease (Mpro) or chymotrypsin-like cysteine protease (3CLpro) and papain-like protease (PLpro) serve as attractive drug targets. Material and methods We screened a library of 2267 natural compounds against Mpro and PLpro using high throughput virtual screening (HTVS). Fifty top-scoring compounds against each protein in HTVS were further evaluated by standard-precision (SP) docking. Compounds with SP docking energy of ≤ –8.0 kcal/mol against Mpro and ≤ –5.0 kcal/mol against PLpro were subjected to extra-precision (XP) docking. Finally, six compounds against each target proteins were identified and subjected to Prime/MM-GBSA free energy calculations. Compounds with the lowest Prime/MM-GBSA energy were subjected to molecular dynamics simulation to evaluate the stability of protein-ligand complexes. Results Proanthocyanidin and rhapontin were identified as the most potent inhibitors of Mpro and PLpro, respectively. Analysis of protein-inhibitor interaction revealed that both protein-inhibitor complexes were stabilized by hydrogen bonding and hydrophobic interactions. Proanthocyanidin interacted with the catalytic residues (His41 and Cys145) of Mpro, while rhapontin contacted the active site residues (Trp106, His272, Asp286) of PLpro. The docking energies of proanthocyanidin and rhapontin towards their respective targets were –10.566 and –10.022 kcal/mol. Conclusions This study’s outcome may support application of proanthocyanidin and rhapontin as a scaffold to build more potent inhibitors with desirable drug-like properties. However, it requires further validation by in vitro and in vivo studies.

Increasing incidence of multi-drug resistant bacterial pathogens, especially in clinical settings, has been developed into a grave health situation. The drug resistance problem demands the necessity for alternative unique therapeutic policies. One such tactic is targeting the quorum sensing (QS) controlled virulence and biofilm production. In this study, we evaluated a marine steroid Siphonocholin (Syph-1) isolated from Siphonochalina siphonella against Chromobacterium violaceum (CV) 12472, Pseudomonas aeruginosa (PAO1), Methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii (BAA) for biofilm and pellicle formation inhibition, and anti-QS property. MIC of Syph-1 against MRSA, CV, PAO1 was found as 64 µg/mL and 256 µg/mL against BAA. At selected sub-MICs, Syph-1 significantly (P ≤ 0.05) decreased the production of QS regulated virulence functions of CV12472 (violacein) and PAO1 [elastase, total protease, pyocyanin, chitinase, exopolysaccharides, and swarming motility]. The Syph-1 significantly decreased (p = 0.005) biofilm formation ability of tested bacterial pathogens, at sub-MIC level (PAO1 > MRSA > CV > BAA) and pellicle formation in A. baumannii (at 128 µg/mL). Molecular docking and simulation results indicated that Siph-1 was bound at the active site of BfmR N-terminal domain with high affinity. This study highlights the anti-QS and anti-biofilm activity of Syph-1 against bacterial pathogens reflecting its broad spectrum anti-infective potential.

Lactoferrin (LF), a multifunctional glycoprotein found in mammalian milk and various exocrine secretions, plays a pivotal role in modulating various responses. Lactoferrin plays a significant role in type-2 diabetes by improving hepatic insulin resistance and pancreatic dysfunction however, the exact mechanism for this improvement is not thoroughly elucidated. To this date, there are no evidence that attributes the direct interaction of lactoferrin with components of NF-κB pathway. Considering this precedent, the current study aimed to investigate the interaction of LF with key components of NF-κB pathway using molecular docking and simulation approaches. Results indicated that LF has shown highly stable interactions with IL-1β, IL-6, IκBα and NF-κB, and relatively weaker interactions with IKK and TNF-α. All four trajectories, including root mean square of deviations (RMSD), root mean square of fluctuation (RMSF), hydrogen bond interactions, and radius of gyration (RoG), confirmed the stable interactions of LF with NF-κB pathway components. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) analysis further supports their stable interactions. To the best of our knowledge, this is the first study to provide convincing evidence that LF can interact with all six major components of the NF-κB pathway. This study provides pioneering in-silico evidence that lactoferrin (LF) can interact with all six major components of the NF-κB pathway, demonstrating highly stable interactions with IL-1β, IL-6, IκBα, and NF-κB, and relatively weaker interactions with IKK and TNF-α. These findings suggest that LF and its peptides have significant potential for both preventive and therapeutic applications by targeting the NF-κB pathway to inhibit inflammation, thereby improving insulin sensitivity and aiding in the management of diabetes., Competing Interests: The authors of this manuscript declared that they have no potential conflict of interest., (© 2024 The Authors. Published by Elsevier Ltd.)

The global demand for therapeutic prebiotics persuades the quest for novel exopolysaccharides that can retard the growth of pathobionts and healthcare-associated pathogens. In this regard, an exopolysaccharide (3.69 mg/mL) producing strain showing prebiotic and antibiofilm activity was isolated from indigenous pineapple pomace of Tripura and identified as Bacillus subtilis PR-C18. Zymogram analysis revealed EPS PR-C18 was synthesized by levansucrase (∼57 kDa) with a maximal activity of 4.62 U/mg. Chromatography techniques, FTIR, and NMR spectral data revealed the homopolymeric nature of purified EPS with a molecular weight of 3.40 × 104 Da. SEM and rheological study unveiled its microporous structure and shear-thinning effect. Furthermore, EPS PR-C18 showed remarkable emulsification, flocculation, water retention, water solubilization, and antioxidant activity. DSC-TGA data demonstrated its high thermostability and cytotoxicity analysis verified its nontoxic biocompatible nature. In addition, the antibiofilm activity of EPS PR-C18 was validated using molecular docking, molecular simulation, MM-GBSA and PCA studies, which exhibited its strong binding affinity (−20.79 kcal/moL) with PelD, a virulence factor from Pseudomonas aeruginosa. Together, these findings support the future exploitation of EPS PR-C18 as an additive or adjuvant in food and pharmaceutical sectors. [Display omitted] [ABSTRACT FROM AUTHOR]

Bacteria expressing New Delhi metallo-β-lactamase-1 (NDM-1) can hydrolyze β-lactam antibiotics (penicillins, cephalosporins, and carbapenems) and, thus, mediate multidrug resistance. The worldwide dissemination of NDM-1 poses a serious threat to public health, imposing a huge economic burden in the development of new antibiotics. Thus, there is an urgent need for the identification of novel NDM-1 inhibitors from a pool of already-known drug molecules. Here, we screened a library of FDA-approved drugs to identify novel non-β-lactam ring-containing inhibitors of NDM-1 by applying computational as well as in vitro experimental approaches. Different steps of high-throughput virtual screening, molecular docking, molecular dynamics simulation, and enzyme kinetics were performed to identify risedronate and methotrexate as the inhibitors with the most potential. The molecular mechanics/generalized Born surface area (MM/GBSA) and molecular dynamics (MD) simulations showed that both of the compounds (risedronate and methotrexate) formed a stable complex with NDM-1. Furthermore, analyses of the binding pose revealed that risedronate formed two hydrogen bonds and three electrostatic interactions with the catalytic residues of NDM-1. Similarly, methotrexate formed four hydrogen bonds and one electrostatic interaction with NDM-1’s active site residues. The docking scores of risedronate and methotrexate for NDM-1 were –10.543 kcal mol−1 and −10.189 kcal mol−1, respectively. Steady-state enzyme kinetics in the presence of risedronate and methotrexate showed a decreased catalytic efficiency (i.e., kcat/Km) of NDM-1 on various antibiotics, owing to poor catalytic proficiency and affinity. The results were further validated by determining the MICs of imipenem and meropenem in the presence of risedronate and methotrexate. The IC50 values of the identified inhibitors were in the micromolar range. The findings of this study should be helpful in further characterizing the potential of risedronate and methotrexate to treat bacterial infections.

The recent dissemination of SARS-CoV-2 from Wuhan city to all over the world has created a pandemic. COVID-19 has cost many human lives and created an enormous economic burden. Although many drugs/vaccines are in different stages of clinical trials, still none is clinically available. We have screened a marine seaweed database (1110 compounds) against 3CLpro of SARS-CoV-2 using computational approaches. High throughput virtual screening was performed on compounds, and 86 of them with docking score < − 5.000 kcal mol−1 were subjected to standard-precision docking. Based on binding energies (< − 6.000 kcal mol−1), 9 compounds were further shortlisted and subjected to extra-precision docking. Free energy calculation by Prime-MM/GBSA suggested RC002, GA004, and GA006 as the most potent inhibitors of 3CLpro. An analysis of ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties of RC002, GA004, and GA006 indicated that only RC002 (callophysin A, from red alga Callophycus oppositifolius) passed Lipinski's, Veber's, PAINS and Brenk's filters and displayed drug-like and lead-like properties. Analysis of 3CLpro-callophysin A complex revealed the involvement of salt bridge, hydrogen bonds, and hydrophobic interactions. callophysin A interacted with the catalytic residues (His41 and Cys145) of 3CLpro; hence it may act as a mechanism-based competitive inhibitor. Docking energy and docking affinity of callophysin A towards 3CLpro was − 8.776 kcal mol−1 and 2.73 × 106 M−1, respectively. Molecular dynamics simulation confirmed the stability of the 3CLpro-callophysin A complex. The findings of this study may serve as the basis for further validation by in vitro and in vivo studies. [ABSTRACT FROM AUTHOR]

Increasing incidence of multi-drug resistant bacterial pathogens, especially in clinical settings, has been developed into a grave health situation. The drug resistance problem demands the necessity for alternative unique therapeutic policies. One such tactic is targeting the quorum sensing (QS) controlled virulence and biofilm production. In this study, we evaluated a marine steroid Siphonocholin (Syph-1) isolated from Siphonochalina siphonella against Chromobacterium violaceum (CV) 12472, Pseudomonas aeruginosa (PAO1), Methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii (BAA) for biofilm and pellicle formation inhibition, and anti-QS property. MIC of Syph-1 against MRSA, CV, PAO1 was found as 64 µg/mL and 256 µg/mL against BAA. At selected sub-MICs, Syph-1 significantly (P ≤ 0.05) decreased the production of QS regulated virulence functions of CV12472 (violacein) and PAO1 [elastase, total protease, pyocyanin, chitinase, exopolysaccharides, and swarming motility]. The Syph-1 significantly decreased (p = 0.005) biofilm formation ability of tested bacterial pathogens, at sub-MIC level (PAO1 > MRSA > CV > BAA) and pellicle formation in A. baumannii (at 128 µg/mL). Molecular docking and simulation results indicated that Siph-1 was bound at the active site of BfmR N-terminal domain with high affinity. This study highlights the anti-QS and anti-biofilm activity of Syph-1 against bacterial pathogens reflecting its broad spectrum anti-infective potential. [ABSTRACT FROM AUTHOR]

• Anti-inflammatory role of Trachyspermum ammi essential oil (TAEO). • TAEO lower lipopolysaccharide induced nitric oxide synthesis in macrophages. • TAEO downregulates inducible nitric oxide synthase & hem oxygenase-1expression. • A cyclooxygenase-2 inhibition activity (in vitro & in silico) displayed by TAEO. This study presents the anti-inflammatory potential of Trachyspermum ammi essential oil (TAEO) against Escherichia coli lipopolysaccharide (LPS)-induced inflammation in RAW 264.7 macrophages. TAEO displayed the anti-inflammatory activity by reducing nitric oxide production and impact on the expression of nitric oxide synthases (iNOS), cyclooxygenase-2 (COX-2), and heme oxygenase-1 (HO-1). Besides, TAEO effectively inhibited the COX-2 enzyme activity with IC 50 value at 4.49 μg/mL. Furthermore, the molecular docking and simulation studies suggest a strong interaction between COX-2 and the important TAEO components thymol, (-5.88 kcal/mol) and carvacrol (-6.30 kcal/mol). The thymol and carvacrol docked complexes are stabilized by hydrogen bonds (at alanine 188 and tyrosine 371) and several hydrophobic interactions at phenylalanine 196, tyrosine 371, tryptophan 373, and leucine 376 and alanine 185, alanine 188, phenylalanine 196, tryptophan 373, leucine 376, and leucine 377, respectively. These results collectively suggest the anti-inflammatory role of TAEO. [ABSTRACT FROM AUTHOR]

The high risk of morbidity and mortality associated with SARS-CoV-2 has accelerated the development of many potential vaccines. However, these vaccines are designed against SARS-CoV-2 isolated in Wuhan, China, and thereby may not be effective against other SARS-CoV-2 variants such as the United Kingdom variant (VUI-202012/01). The UK SARS-CoV-2 variant possesses D614G mutation in the Spike protein, which impart it a high rate of infection. Therefore, newer strategies are warranted to design novel vaccines and drug candidates specifically designed against the mutated forms of SARS-CoV-2. One such strategy is to target ACE2 (angiotensin-converting enzyme2)–Spike protein RBD (receptor binding domain) interaction. Here, we generated a homology model of Spike protein RBD of SARS-CoV-2 UK strain and screened a marine seaweed database employing different computational approaches. On the basis of high-throughput virtual screening, standard precision, and extra precision molecular docking, we identified BE011 (Dieckol) as the most potent compounds against RBD. However, Dieckol did not display drug-like properties, and thus different derivatives of it were generated in silico and evaluated for binding potential and drug-like properties. One Dieckol derivative (DK07) displayed good binding affinity for RBD along with acceptable physicochemical, pharmacokinetic, drug-likeness, and ADMET properties. Analysis of the RBD–DK07 interaction suggested the formation of hydrogen bonds, electrostatic interactions, and hydrophobic interactions with key residues mediating the ACE2–RBD interaction. Molecular dynamics simulation confirmed the stability of the RBD–DK07 complex. Free energy calculations suggested the primary role of electrostatic and Van der Waals’ interaction in stabilizing the RBD–DK07 complex. Thus, DK07 may be developed as a potential inhibitor of the RBD–ACE2 interaction. However, these results warrant further validation by in vitro and in vivo studies.

Human α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (hACMSD) is a zinc containing amidohydrolase which is a vital enzyme of the kynurenine pathway in tryptophan metabolism. It prevents the accumulation of quinolinic acid (QA) and helps in the maintenance of basal Trp-niacin ratio. To assess the structure based inhibitory action of PAEs such as DMP, DEP, DBP, DIBP, DEHP and their metabolites, these were docked into the active site cavity of hACMSD. Docking results show that the binding affinities of PAEs lie in the comparable range (−4.9 kca/mol–7.48 kcal/mol) with Dipicolinic acid (−6.21 kcal/mol), a substrate analogue of hACMSD. PAEs interact with the key residues such as Arg47 and Trp191 and lie within the 4 Å vicinity of zinc metal at the active site of hACMSD. Dynamics and stability of the PAEs-hACMSD complexes were determined by performing molecular dynamics simulations using GROMACS 5.14. Binding free energy calculations of the PAEs-hACMSD complexes were estimated by using MMPBSA method. The results emphasize that PAEs can structurally mimic the binding pattern of tryptophan metabolites to hACMSD, which further leads to inhibition of its activity and accumulation of the quinolate in the kynurenine pathway of tryptophan metabolism. [ABSTRACT FROM AUTHOR]

Valproic acid (VA) is a proven inhibitor of human histone deacetylases (HDACs). The homogenous HDAC has been associated with all major human parasitic pathogens and hence, it has been considered an attractive drug target for anti-leishmanial therapy. To assist in drug design endeavors for HDACs, an in- vitro study has been presented to investigate the VA inhibition on Leishmania donovani HDAC ( Ld HDAC). The regression analysis of VA by 24 hrs viability assay confirmed its activity against Ld HDAC. Moreover, the toxicity of VA is also well documented. Thus, the in-silico experiments were also conducted to screen the non-toxic VA derivatives as anti-leishmanial drug candidates having potential as inhibitors of Ld HDAC. For in-silico study, the 3D structure of target Ld HDAC was developed by homology modeling. Based on their in-silico activity, we shortlisted 13 VA derivatives having maximum affinity for Ld HDAC and identified four potential derivatives that can specifically bind to this protein. After that, these ligands were subjected to molecular dynamics simulation. These derivatives may be effective against L. donovani promastigotes since they followed Lipinski's RO5 and were non-toxic. Thus, screened derivatives can be considered as lead ligands for targeting Ld HDAC and may be used as possible drug candidates to treat leishmaniasis and overcome the limitation of anti-leishmanial drugs. This is the first report of antileishmanial potential of VA and its derivatives targeting Ld HDAC. Hence, the current investigation presents a search for novel target specific drugs to aid the anti-leishmanial drug development.Communicated by Ramaswamy H. Sarma.

The intake of quercetin and its glycosides has been proven to effectively reduce the level of high mobility group protein 1 (HMGB1) and the degree of inflammation, but the underlying structural mechanism is still unclear. In this study, the direct interaction between HMGB 1 and quercetin, isoquercitrin, and rutin was recorded by surface plasmon resonance (SPR). The binding interactions led to the intrinsic fluorescence quenching of HMGB1 through static quenching mechanism based on fluorescence spectroscopy. Circular dichroism (CD) spectra showed a decrease in α-helical content of HMGB1 with a slight impact on the thermal stability of HMGB1. Furthermore, molecular simulations displayed three flavonoids-HMGB1 complexes maintained primarily by hydrogen bond and hydrophobic force, confirming the strong association with Phe14. Besides, co-treatment of quercetin could significantly ameliorate HMGB1-stimulated nitric oxide release in RAW264.7 cells. These intrinsic characteristics on the interaction of quercetin, isoquercitrin, and rutin with HMGB1 protein could be conducive to understanding the molecular mechanisms of flavonoids in HMGB1-related inflammatory diseases. • Quercetin, isoquercitrin, rutin showed a direct interaction with HMGB1. • Three flavonoids led to changes of HMGB1's hydrophobicity and spatial conformation. • Three complexes were maintained by hydrogen bonding and hydrophobic interactions. • Co-treatment with quercetin and derivatives reduced HMGB1-stimulated inflammation. [ABSTRACT FROM AUTHOR]

ARHI, a putative tumor suppressor protein with unique 32 amino acid extension in the N-terminal region, differs from oncogenes Ras and Rap, negatively regulates STAT3 signaling and inhibits the migration of ovarian cancer cells. ARHI associates directly with STAT3, also forms complex with importinβ, and prevents formation of RanGTPase–importinβ complex, which is essential for transporting STAT3 into the nucleus. Hence, the structural aspects pertaining to ARHI mediated inhibition of STAT3 translocation can provide hints on the regulation of STAT3 signaling mechanism. Accordingly, in the present study, the structure of ARHI was predicted and its transition from inactive to active state studied using MD simulations and free energy landscape analysis. The transition of ARHI is marked by the movement of switch I region towards γ-phosphate of GTP, in addition, the hydrophobic interaction between N-terminal helix and switch II region of ARHI accounts for its low intrinsic GTPase activity. Further, the protein–protein interaction studies reveal that the residues of N-terminal helix, effector domain, P-loop and G box motif of ARHI actively form polar and non-polar interaction with NTD of STAT3 and make them compact thereby rendering STAT3 inaccessible for Ran–importinβ mediated translocation. On the other hand, ARHI competes with RanGTPase and interacts with importinβ via basic–acidic patch interaction, which leads to inhibition of STAT3 translocation. The interacting residues involved for this structural mechanism would be instrumental in designing inhibitors for STAT3, which mimics ARHI thereby leading to the suppression of cancer cell growth. [ABSTRACT FROM AUTHOR]

The worldwide pandemic of coronavirus disease 2019 (COVID-19) along with the various newly discovered major SARS-CoV-2 variants, including B.1.1.7, B.1.351, and B.1.1.28, constitute the Variant of Concerns (VOC). It's difficult to keep these variants from spreading over the planet. As a result of these VOCs, the fifth wave has already begun in several countries. The rapid spread of VOCs is posing a serious threat to human civilization. There is currently no specific medicine available for the treatment of COVID-19. Here, we present the findings of methods that used a combination of structure-assisted drug design, virtual screening, and high-throughput screening to swiftly generate lead compounds against Mpro protein of SARs-CoV-2. Therapeutics, in addition to vaccinations, are an essential element of the healthcare response to COVID-19's persistent threat. In the current study, we designed the efficient compounds that may combat all emerging variants of SARs-CoV-2 by targeting the common Mpro protein. The present study was aimed to discover new compounds that may be proposed as new therapeutic agents to treat COVID-19 infection without any adverse effects. For this purpose, a computational-based virtual screening of 352 in-house synthesized compounds library was performed through molecular docking and Molecular Dynamics (MD) simulation approach. As a result, four novel potent compounds were successfully shortlisted by implementing certain pharmacological, physiological, and ADMET criteria i.e., compounds 3, 4, 21, and 22. Furthermore, MD simulations were performed to evaluate the stability and dynamic behavior of these compounds with Mpro complex for about 30 ns. Eventually, compound 22 was found to be highly potent against Mpro protein and was further evaluated by applying 100 ns simulations. Our findings showed that these shortlisted compounds may have potency to treat the COVID-19 infection for which further experimental validation is proposed as part of a follow-up investigation., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Among the many abnormally expressed proteins in ovarian cancer, the prominent cancer in women, ID1 (inhibitors of DNA binding protein 1) is a potential one among other several targets. Interaction of ID1 with ETS-1 (transcriptional activator of p16) suppresses the transcription of p16 and causes abnormal cell proliferation. A peptide aptamer (ID1/3-PA7) has been designed to prevent this interaction and thereby leading to the transcription of p16. However, the structural basis behind the molecular interaction of ID1 with ETS-1 (agonist) and ID1/3-PA7 (antagonist) is poorly understood. In order to understand this structural recognition and their interaction mechanism, in silico methods were used. From this interaction analysis, the residues of ETS-1 involved in interaction with the p16 promoter were found to be targeted by ID1. Subsequently, ETS-1 binding residues of ID1 were found to be targeted by its aptamer- ID1/3-PA7. These results suggest that both ETS-1 and ID1/3-PA7 binds at the same region harbored by the residues-H97, D100, R103, D104, L107, A144, C145, D149, D150 and C154 of ID1. All these observations correlate with the experimental reports, suggesting that the identified residues might play a crucial role in promulgating the oncogenic effects of ID1. In silico alanine scanning mutagenesis also confirms the role of identified hot spot residues in p16 regulation. Finally, the molecular dynamic simulation studies reveal the prolonged stability of the aforementioned interacting complexes. The obtained results throw light on the structure and residues of ID1 involved in transcriptional regulation of p16. [ABSTRACT FROM AUTHOR]

Bacteria expressing New Delhi metallo-β-lactamase-1 (NDM-1) can hydrolyze β-lactam antibiotics (penicillins, cephalosporins, and carbapenems) and, thus, mediate multidrug resistance. The worldwide dissemination of NDM-1 poses a serious threat to public health, imposing a huge economic burden in the development of new antibiotics. Thus, there is an urgent need for the identification of novel NDM-1 inhibitors from a pool of already-known drug molecules. Here, we screened a library of FDA-approved drugs to identify novel non-β-lactam ring-containing inhibitors of NDM-1 by applying computational as well as in vitro experimental approaches. Different steps of high-throughput virtual screening, molecular docking, molecular dynamics simulation, and enzyme kinetics were performed to identify risedronate and methotrexate as the inhibitors with the most potential. The molecular mechanics/generalized Born surface area (MM/GBSA) and molecular dynamics (MD) simulations showed that both of the compounds (risedronate and methotrexate) formed a stable complex with NDM-1. Furthermore, analyses of the binding pose revealed that risedronate formed two hydrogen bonds and three electrostatic interactions with the catalytic residues of NDM-1. Similarly, methotrexate formed four hydrogen bonds and one electrostatic interaction with NDM-1's active site residues. The docking scores of risedronate and methotrexate for NDM-1 were –10.543 kcal mol−1 and −10.189 kcal mol−1, respectively. Steady-state enzyme kinetics in the presence of risedronate and methotrexate showed a decreased catalytic efficiency (i.e., kcat/Km) of NDM-1 on various antibiotics, owing to poor catalytic proficiency and affinity. The results were further validated by determining the MICs of imipenem and meropenem in the presence of risedronate and methotrexate. The IC50 values of the identified inhibitors were in the micromolar range. The findings of this study should be helpful in further characterizing the potential of risedronate and methotrexate to treat bacterial infections. [ABSTRACT FROM AUTHOR]

Medulloblastoma (MB) is a primary central nervous system tumor affecting mainly young children. New strategies of drug delivery are urgent to treat MB and, in particular, the SHH-dependent subtype—the most common in infants—in whom radiotherapy is precluded due to the severe neurological side effects. Plant virus nanoparticles (NPs) represent an innovative solution for this challenge. Tomato bushy stunt virus (TBSV) was functionally characterized as a carrier for drug targeted delivery to a murine model of Shh-MB. The TBSV NPs surface was genetically engineered with peptides for brain cancer cell targeting, and the modified particles were produced on a large scale using Nicotiana benthamiana plants. Tests on primary cultures of Shh-MB cells allowed us to define the most efficient peptides able to induce specific uptake of TBSV. Immunofluorescence and molecular dynamics simulations supported the hypothesis that the specific targeting of the NPs was mediated by the interaction of the peptides with their natural partners and reinforced by the presentation in association with the virus. In vitro experiments demonstrated that the delivery of Doxorubicin through the chimeric TBSV allowed reducing the dose of the chemotherapeutic agent necessary to induce a significant decrease in tumor cells viability. Moreover, the systemic administration of TBSV NPs in MB symptomatic mice, independently of sex, confirmed the ability of the virus to reach the tumor in a specific manner. A significant advantage in the recognition of the target appeared when TBSV NPs were functionalized with the CooP peptide. Overall, these results open new perspectives for the use of TBSV as a vehicle for the targeted delivery of chemotherapeutics to MB in order to reduce early and late toxicity. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders are illnesses that are responsible for neuronal cell death and resulting in lifelong cognitive problems. Due to their unclear mechanism, there are no effective drugs available for the treatment. For a long time, herbal drugs have been used as a role model in the field of the drug discovery process. Withania somnifera (Ashwagandha) in the Indian medicinal system (Ayurveda) is used for several neuronal disorders like insomnia and memory loss for decades. This study aims to identify active components of W. somnifera (WS) as potential inhibitors for the treatment of neurodegenerative diseases (ND). To fulfill this objective, Network pharmacology approach, gene ontology, pharmacokinetics analysis, molecular docking, and molecular dynamics simulation (MDS) studies were performed. A total of 77 active components in WS, 175 predicted neurodegenerative targets of WS, and 8085 ND-related targets were identified from different databases. The network analysis showed that the top ten targets APP, EGFR, MAPK1, ESR1, HSPA4, PRKCD, MAPK3, ABL1, JUN, and GSK3B were found as significant target related to ND. On the basis of gene ontology and topology analysis results, APP was found as a significant target related to Alzheimer's disease pathways. Molecular docking results found that Anahygrine, Cuscohygrine, Isopelletierine, and Nicotine showed the best binding affinities -5.55, -4.73, -4.04, and -4.11 Kcal/mol. Further, MDS results suggested that Isopelletierine and Nicotine could be used as potential inhibitors against APP protein and could be useful for the treatment of Alzheimer's disease.Communicated by Ramaswamy H. Sarma.

COVID-19 caused by SARS-CoV-2 has emerged as a potential threat to human life, especially to people suffering from chronic diseases. In this study, we investigated the ability of selected FDA-approved drugs to inhibit TACE (tumor necrosis factor α converting enzyme), which is responsible for the shedding of membrane-bound ACE2 (angiotensin-converting enzyme2) receptors into soluble ACE2. The inhibition of TACE would lead to an increased population of membrane-bound ACE2, which would facilitate ACE2-Spike protein interaction and viral entry. A total of 50 drugs prescribed in treating various chronic diseases in Saudi Arabia were screened by performing molecular docking using AutoDock4.2. Based on docking energy (≤ -9.00 kcal mol -1 ), four drugs (Celecoxib, Glipizide, Lapatinib, and Sitagliptin) were identified as potential inhibitors of TACE, with binding affinities up to 10 6 -10 7 M -1 . Analysis of the molecular docking suggests that these drugs were bound to TACE's catalytic domain and interact with the key residues such as His405, Glu406, and His415, which are involved in active site Zn 2+ ion chelation. Molecular dynamics simulation was performed to confirm the stability of TACE-drugs complexes. RMSD (root mean square deviation), RMSF (root mean square fluctuation), Rg (radius of gyration), and SASA (solvent accessible surface area) were within the acceptable limits. Free energy calculations using Prime-MM/GBSA suggest that Celecoxib formed the most stable complex with TACE, followed by Glipizide, Sitagliptin, and Lapatinib. The finding of this study suggests a mechanism for drugs to aggravate SARS-CoV-2 infection and hence high mortality in patients suffering from chronic diseases.Communicated by Ramaswamy H. Sarma.

The high risk of morbidity and mortality associated with SARS-CoV-2 has accelerated the development of many potential vaccines. However, these vaccines are designed against SARS-CoV-2 isolated in Wuhan, China, and thereby may not be effective against other SARS-CoV-2 variants such as the United Kingdom variant (VUI-202012/01). The UK SARS-CoV-2 variant possesses D614G mutation in the Spike protein, which impart it a high rate of infection. Therefore, newer strategies are warranted to design novel vaccines and drug candidates specifically designed against the mutated forms of SARS-CoV-2. One such strategy is to target ACE2 (angiotensin-converting enzyme2)–Spike protein RBD (receptor binding domain) interaction. Here, we generated a homology model of Spike protein RBD of SARS-CoV-2 UK strain and screened a marine seaweed database employing different computational approaches. On the basis of high-throughput virtual screening, standard precision, and extra precision molecular docking, we identified BE011 (Dieckol) as the most potent compounds against RBD. However, Dieckol did not display drug-like properties, and thus different derivatives of it were generated in silico and evaluated for binding potential and drug-like properties. One Dieckol derivative (DK07) displayed good binding affinity for RBD along with acceptable physicochemical, pharmacokinetic, drug-likeness, and ADMET properties. Analysis of the RBD–DK07 interaction suggested the formation of hydrogen bonds, electrostatic interactions, and hydrophobic interactions with key residues mediating the ACE2–RBD interaction. Molecular dynamics simulation confirmed the stability of the RBD–DK07 complex. Free energy calculations suggested the primary role of electrostatic and Van der Waals' interaction in stabilizing the RBD–DK07 complex. Thus, DK07 may be developed as a potential inhibitor of the RBD–ACE2 interaction. However, these results warrant further validation by in vitro and in vivo studies. [ABSTRACT FROM AUTHOR]

Introduction: The emergence of a new and highly pathogenic coronavirus (SARS-CoV-2) in Wuhan (China) and its spread worldwide has resulted in enormous social and economic losses. Amongst many proteins encoded by the SARS-CoV-2 genome, the main protease (Mpro) or chymotrypsin-like cysteine protease (3CLpro) and papain-like protease (PLpro) serve as attractive drug targets., Material and Methods: We screened a library of 2267 natural compounds against Mpro and PLpro using high throughput virtual screening (HTVS). Fifty top-scoring compounds against each protein in HTVS were further evaluated by standard-precision (SP) docking. Compounds with SP docking energy of ≤ -8.0 kcal/mol against Mpro and ≤ -5.0 kcal/mol against PLpro were subjected to extra-precision (XP) docking. Finally, six compounds against each target proteins were identified and subjected to Prime/MM-GBSA free energy calculations. Compounds with the lowest Prime/MM-GBSA energy were subjected to molecular dynamics simulation to evaluate the stability of protein-ligand complexes., Results: Proanthocyanidin and rhapontin were identified as the most potent inhibitors of Mpro and PLpro, respectively. Analysis of protein-inhibitor interaction revealed that both protein-inhibitor complexes were stabilized by hydrogen bonding and hydrophobic interactions. Proanthocyanidin interacted with the catalytic residues (His41 and Cys145) of Mpro, while rhapontin contacted the active site residues (Trp106, His272, Asp286) of PLpro. The docking energies of proanthocyanidin and rhapontin towards their respective targets were -10.566 and -10.022 kcal/mol., Conclusions: This study's outcome may support application of proanthocyanidin and rhapontin as a scaffold to build more potent inhibitors with desirable drug-like properties. However, it requires further validation by in vitro and in vivo studies., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2021 Termedia & Banach.)

Background: With the burgeoning worldwide aging population, the incidence of Alzheimer's disease (AD) and its associated disorders is continuously rising. To appraise other relevant drug targets that could lead to potent enzyme targeting, 13 previously predicted ligands (shown favorable binding with AChE (acetylcholinesterase) and GSK-3 (glycogen synthase kinase) were screened for targeting 3 different enzymes, namely butyrylcholinesterase (BChE), monoamine oxidase A (MAO-A), and monoamine oxidase B (MAO-B) to possibly meet the unmet medical need of better AD treatment., Materials and Methods: The study utilized in silico screening of 13 ligands against BChE, MAO-A and MAOB using PyRx-Python prescription 0.8. The visualization of the active interaction of studied compounds with targeted proteins was performed by Discovery Studio 2020 (BIOVIA)., Results: The computational screening of studied ligands revealed the docking energies in the range of -2.4 to -11.3 kcal/mol for all the studied enzymes. Among the 13 ligands, 8 ligands (55E, 6Z2, 6Z5, BRW, F1B, GVP, IQ6, and X37) showed the binding energies of ≤ -8.0 kcal/mol towards BChE, MAO-A and MAO-B. The ligand 6Z5 was found to be the most potent inhibitor of BChE and MAO-B, with a binding energy of -9.7 and -10.4 kcal mol, respectively. Molecular dynamics simulation of BChE-6Z5 and MAO-B-6Z5 complex confirmed the formation of a stable complex., Conclusion: Our computational screening, molecular docking, and molecular dynamics simulation studies revealed that the above-mentioned enzymes targeted ligands might expedite the future design of potent anti-AD drugs generated on this chemical scaffold., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The bacteria expressing New Delhi Metallo-β-lactamase-1 (NDM-1) can hydrolyze all β-lactam antibiotics including carbapenems, causing multi-drug resistance. The worldwide emergence and dissemination of gene blaNDM-1 (produces NDM-1) in hospital and community settings, rising problems for public health. Indeed, there is an urgent need for NDM-1 inhibitors to manage antibiotic resistance. Here, we have identified novel non-β-lactam ring-containing inhibitors of NDM-1 by applying a high-throughput virtual screening of lead-like subset of ZINC database. The screened compounds were followed for the molecular docking, the molecular dynamics simulation, and then enzyme kinetics assessment. The adopted screening procedure funnels out five novel inhibitors of NDM-1 including ZINC10936382, ZINC30479078, ZINC41493045, ZINC7424911, and ZINC84525623. The molecular mechanics-generalized born surface area and molecular dynamics (MD) simulation showed that ZINC84525623 formed the most stable complex with NDM-1. Furthermore, analyses of the binding pose after MD simulation revealed that ZINC84525623 formed two hydrogen bonds (electrostatic and hydrophobic interaction) with key amino acid residues of the NDM-1 active site. The docking binding free energy and docking binding constant for the ZINC84525623 and NDM-1 interaction were estimated to be −11.234 kcal/mol, and 1.74 × 108 M−1 respectively. Steady-state enzyme kinetics in the presence of ZINC84525623 show the decreased catalytic efficiency (i.e., kcat/Km) of NDM-1 on various antibiotics. The findings of this study would be helpful in identifying novel inhibitors against other β-lactamases from a pool of large databases. Furthermore, the identified inhibitor (ZINC84525623) could be developed as efficient drug candidates. [ABSTRACT FROM AUTHOR]

We report the aggregation and photophysical properties of a pyridothiazole-based, aggregation-induced, emission-enhancement (AIEE) luminogen 4-(5-methoxy-thiazolo[4,5- b ]pyridin-2-yl)benzoic acid (PTC1) and its application for the sensitive detection and monitoring of amyloid fibrillation. The aggregation properties of the AIEE probe were extensively studied by atomic force microscopy (AFM) and dynamic light scattering (DLS), and it was noted that as aggregation increases the fluorescence of PTC1 also was increased. The fluorescence of PTC1 was quenched upon the addition of cupric (Cu 2+ ) ions, while the fluorescence is regenerated in the presence of amyloid fibers. AFM studies reveal that the PTC1 molecules self-associate/aggregate to hairy micelle-like structures, which dissociate or disrupt in the presence of the Cu 2+ ions and again reassemble in the presence of amyloid fibers. Hence, the quenching and regeneration of PTC1 fluorescence may be attributed to the disaggregation and aggregation-induced emission (AIE), respectively. Further, a comparative analysis of the performance of PTC1 was done with conventional Thioflavin T, which confirms it to be a more sensitive probe for the detection of the amyloid, both in the presence and absence of Cu 2+ ions. The experimental results were also validated theoretically via molecular docking and simulation studies. Of note, a very simple, facile, and cost-effective methodology for the detection of the amyloid fibers is presented, wherein fluorescence quenching/enhancement can be visualized under the UV light without the use of sophisticated instrumentation techniques. The AIEE probe was designed using an unusual pyridothiazole scaffold unlike commonly used archetypal AIE scaffolds based on tetraphenylethene (TPE) and hexaphenylsilole (HPS). Hence, the work also has implications in designing future AIEE dyes based on the pyridothiazole scaffold reported.

HIV-1 integrase is a unique promising component of the viral replication cycle, catalyzing the integration of reverse transcribed viral cDNA into the host cell genome. Generally, IN activity requires both viral as well as a cellular co-factor in the processing replication cycle. Among them, the human lens epithelium-derived growth factor (LEDGF/p75) represented as promising cellular co-factor which supports the viral replication by tethering IN to the chromatin. Due to its major importance in the early steps of HIV replication, the interaction between IN and LEDGF/p75 has become a pleasing target for anti-HIV drug discovery. The present study involves the finding of novel inhibitor based on the information of dimeric CCD of IN in complex with known inhibitor, which were carried out by applying a structure-based virtual screening concept with molecular docking. Additionally, Free binding energy, ADME properties, PAINS analysis, Density Functional Theory, and Enrichment Calculations were performed on selected compounds for getting a best lead molecule. On the basis of these analyses, the current study proposes top 3 compounds: Enamine-Z742267384, Maybridge-HTS02400, and Specs-AE-848/37125099 with acceptable pharmacological properties and enhanced binding affinity to inhibit the interaction between IN and LEDGF/p75. Furthermore, Simulation studies were carried out on these molecules to expose their dynamics behavior and stability. We expect that the findings obtained here could be future therapeutic agents and may provide an outline for the experimental studies to stimulate the innovative strategy for research community.

The emergence of multi-drug resistant strains and co-occurrence of tuberculosis with HIV creates a major burden to the human health globally. Failure of primary antibacterial therapy necessitates the identification of new mycobacterial drugs. In this study, a comprehensive analysis involving bottom-up systems biology approach was applied wherein we have identified potential therapeutic targets of Mycobacterium tuberculosis infections. Our study prioritized M. tuberculosis therapeutic targets (aspartate-β-semialdeyhde dehydrogenase [ASD], dihydrodipicolinate reductase and diaminopimelate decarboxylase) based on flux and elementary mode analysis using direct mathematical modeling of the relevant metabolic pathways. Molecular docking and simulation studies of the priority target (ie, ASD) revealed the therapeutic potential of the selected natural products (Huperzine A, Rosmarinic acid, and Curcumin) based ASD inhibitors. The study highlights the crucial role of systems biology in conjunction with molecular interaction (docking) for probing novel leads against an increasingly resistant pathogen, M. tuberculousis., (© 2017 Wiley Periodicals, Inc.)