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Citrobacter koseri causes infection in people who are immunocompromised. Without effective antibiotics, these infections can become severe and life-threatening, so effective drugs are essential to treat these infections. Utilizing subtractive genomics, 2699 ORFs were predicted and translated into amino acid sequences. Metabolic pathway analysis and subcellular localization helped define the roles of key bacterial proteins. Two druggable proteins, WP_012000829.1 and WP_275157394.1, were discovered as promising targets. Alpha Fold provided 3D structures, and a library of 1600 echinoderm metabolites was docked against these proteins, with Ampicillin, Levofloxacin, and Doxycycline as controls. Notably, CMNPD13085 and CMNPD15632 exhibited the highest binding affinities for WP_012000829.1 and WP_275157394.1, respectively. Molecular dynamics simulations and MM-GBSA binding free energy complemented docking results. However, acknowledging the reliance on computational validations, the study emphasizes the need for essential in-vitro research to transform these potential inhibitors into therapeutic drugs. [ABSTRACT FROM AUTHOR]

The SARS‐CoV‐2 3C‐like protease (3CLpro) has emerged as a key target for drug development owing to its crucial role in viral replication of SARS‐CoV‐2 virus. In this study, we employed a ligand‐based virtual screening strategy to identify potential small molecules capable of binding to SARS‐CoV‐2 3CLpro. Using GC376 as a reference compound, we conducted a comprehensive search in a chemical database and identified 178 candidate molecules (CPLs) with structural similarity to GC376. Molecular docking analyses revealed that several CPLs exhibited superior binding affinities to SARS‐CoV‐2 3CLpro compared to GC376. Notably, CPL‐390, CPL‐374, and CPL‐306 displayed the highest binding energies, indicating their potential as inhibitors of SARS‐CoV‐2 3CLpro. Detailed analysis of noncovalent interactions and molecular mechanics generalized Born surface area (MMGBSA) calculations further supported the binding affinity of CPLs to SARS‐CoV‐2 3CLpro. Key interactions with catalytic residues and steric hindrance within the binding pocket highlighted potential inhibition mechanisms for CPL‐306, CPL‐374, and CPL‐390. Moreover, pharmacokinetic analysis indicated that CPL‐306, CPL‐374, and CPL‐390 possessed favorable absorption, distribution, metabolism, and excretion (ADME) properties, positioning them as promising candidates for further drug development. In contrast, GC376 exhibited less favorable pharmacological characteristics, emphasizing the need for novel compounds with improved profiles. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of the metabolic syndrome, posing risks to cardiovascular and hepatic health worldwide. Non-alcoholic steatohepatitis (NASH) which is a severe form of NAFLD, has a global prevalence. Therapeutic targets for NASH include THR-β, GLP-1 receptor, PPARα/δ/γ, FGF21 analogs, and FXR, a bile acid nuclear receptor pivotal for regulating bile acid synthesis and excretion. Our study aims to design the non-steroidal FXR agonist for NASH treatment, as FXR's role in the regulation of bile acid processes, rendering it a promising drug target for NASH therapy. Utilizing tropifexor as a reference molecule, we generated a shape-based pharmacophore model with seven features, identifying key binding requirements within the FXR active site. Virtual screening using this model, coupled with molecular docking studies, helped pinpoint potential ligands from diverse small molecule databases. Further analysis via MM/GBSA revealed 12 molecules with binding affinities comparable to tropifexor. Among them, DB15416 exhibited the lowest binding free energy and superior docking scores. To assess its dynamic stability, we subjected DB15416 to molecular dynamics simulations, confirming its suitability as a FXR agonist. These findings suggest that DB15416 holds promise as a FXR agonist for NASH treatment, which can be evaluated by experimental studies. [ABSTRACT FROM AUTHOR]

In the present work, phytoconstituents from Citrus limon are computationally tested against SARS‐CoV‐2 target protein such as Mpro ‐ (5R82.pdb), Spike ‐ (6YZ5.pdb) &RdRp ‐ (7BTF.pdb) for COVID‐19. Docking was done by glide model, QikProp was performed by in silico ADMET screening & Prime MM‐GB/SA modules were used to define binding energy. When compared with approved COVID‐19 drugs such as Remdesivir, Ritonavir, Lopinavir, and Hydroxychloroquine, plant‐based constituents such as Quercetin, Rutoside, Naringin, Eriocitrin, and Hesperidin. bind with significant G‐scores to the active SARS‐CoV‐2 place. The constituents Rutoside and Eriocitrin were studied in each MD simulation in 100 ns against 3 proteins 5R82.pdb, 6YZ5.pdb and 7BTF.pdb.We performed an assay with significant natural compounds from contacts and in silico results (Rutin, Eriocitrin, Naringin, Hesperidin) using 3CL protease assay kit (B.11529 Omicron variant). This kit contained 3CL inhibitor GC376 as Control. The IC50 value of the test compound was found to be Rutin −17.50 μM, Eriocitrin−37.91 μM, Naringin−39.58 μM, Hesperidine−140.20 μM, the standard inhibitory concentration of GC376 was 38.64 μM. The phytoconstituents showed important interactions with SARS‐CoV‐2 targets, and potential modifications could be beneficial for future development. [ABSTRACT FROM AUTHOR]

Nipah virus (NiV) is known to be a highly pathogenic zoonotic virus, which is included in the World Health Organization Research & Development Blueprint list of priority diseases with up to 70% mortality rate. Due to its high pathogenicity and outbreak potency, a therapeutic countermeasure against NiV is urgently needed. As NiV needs to be handled within a Biological Safety Level (BSL) 4 facility, we had developed a safe drug screening platform utilizing a baculovirus expression vector system (BEVS) based on a NiV-induced syncytium formation that could be handled within a BSL-1 facility. To reconstruct the NiV-induced syncytium formation in BEVS, two baculoviruses were generated to express recombinant proteins that are responsible for inducing the syncytium formation, including one baculovirus exhibiting co-expressed NiV fusion protein (NiV-F) and NiV attachment glycoprotein (NiV-G) and another exhibiting human EphrinB2 protein. Interestingly, syncytium formation was observed in infected insect cells when the medium was modified to have a lower pH level and supplemented with cholesterol. Fusion inhibitory properties of several compounds, such as phytochemicals and a polysulfonated naphthylamine compound, were evaluated using this platform. Among these compounds, suramin showed the highest fusion inhibitory activity against NiV-induced syncytium in the baculovirus expression system. Moreover, our in silico results provide a molecular-level glimpse of suramin's interaction with NiV-G's central hole and EphrinB2's G-H loop, which could be the possible reason for its fusion inhibitory activity. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) caused by the Mycobacterium tuberculosis (MTB) pathogen is a serious contagious illness that endangers the public's health. However, TB is treatable but due to the result of ineffective and protracted medication, MDR‐MTB and XDR‐MTB were able to develop, making their eradication highly challenging and necessitating potential treatments to be cured. This study aimed to identify the novel inhibitor for the InhA enzyme, a potential target of MTB. Initially, 2721 phytochemicals libraries were screened for ADME/Tox profiling and 49 phytochemicals were filtered out. Moreover, these phytochemicals with reference inhibitor triclosan were docked against InhA (PDB ID: 1BVR)., were showing binding energies ranging from −9.16–−6.3 kcal/mol, whereas triclosan showed −6.90 kcal/mol of binding energy. The docking results reveal that irilone (−9.16 kcal/mol) and aurantio‐obtusin (−8.84 kcal/mol) exhibit promising binding energy and perfectly occupy the binding site of InhA. Furthermore, molecular dynamics simulation (MDS) and MMGBSA studies showed better affinities of selected compounds in terms of stability, compactness, flexibility, and total BFE in complexes with InhA. This study concluded that irilone and aurantio‐obtusin could be promising InhA inhibitors based on their impressive pharmacokinetic profiling, toxicity, binding affinity, and stability. However experimental validation is a subject of further research. [ABSTRACT FROM AUTHOR]

Cancer is a generic term for a group of disorders defined by uncontrolled cell growth and the potential to invade or spread to other parts of the body. Gene and epigenetic alterations disrupt normal cellular control, leading to abnormal cell proliferation, resistance to cell death, blood vessel development, and metastasis (spread to other organs). One of the several routes that play an important role in the development and progression of cancer is the phosphoinositide 3-kinase (PI3K) signaling pathway. Moreover, the gene PIK3CG encodes the catalytic subunit gamma (p110γ) of phosphoinositide 3-kinase (PI3Kγ), a member of the PI3K family. Therefore, in this study, PIK3CG was targeted to inhibit cancer by identifying a novel inhibitor through computational methods. The study screened 1015 chemical fragments against PIK3CG using machine learning-based binding estimation and docking to select the potential compounds. Later, the analogues were generated from the selected hits, and 414 analogues were selected, which were further screened, and as most potential candidates, three compounds were obtained: (a) 84,332, 190,213, and 885,387. The protein–ligand complex's stability and flexibility were then investigated by dynamic modeling. The 100 ns simulation revealed that 885,387 exhibited the steadiest deviation and constant creation of hydrogen bonds. Compared to the other compounds, 885,387 demonstrated a superior binding free energy (ΔG = −18.80 kcal/mol) with the protein when the MM/GBSA technique was used. The study determined that 885,387 showed significant therapeutic potential and justifies further experimental investigation as a possible inhibitor of the PIK3CG target implicated in cancer. [ABSTRACT FROM AUTHOR]

Allergic rhinitis (AR) is a prevalent inflammatory condition affecting millions globally, with current treatments often associated with significant side effects. To seek safer and more effective alternatives, natural sources like Urtica dioica (UD) are being explored. However, UD's mechanism of action remains unknown. Therefore, to elucidate it, we conducted an in silico evaluation of UD phytochemicals' effects on known therapeutic targets of allergic rhinitis: histamine receptor 1 (HR1), neurokinin 1 receptor (NK1R), cysteinyl leukotriene receptor 1 (CLR1), chemoattractant receptor-homologous molecule expressed on type 2 helper T cells (CRTH2), and bradykinin receptor type 2 (BK2R). The docking analysis identified amentoflavone, alpha-tocotrienol, neoxanthin, and isorhamnetin 3-O-rutinoside as possessing a high affinity for all the receptors. Subsequently, molecular dynamics (MD) simulations were used to analyze the key interactions; the free energy of binding was calculated through Generalized Born and Surface Area Solvation (MMGBSA), and the conformational changes were evaluated. Alpha-tocotrienol exhibited a high affinity while also inducing positive conformational changes across all targets. Amentoflavone primarily affected CRTH2, neoxanthin targeted NK1R, CRTH2, and BK2R, and isorhamnetin-3-O-rutinoside acted on NK1R. These findings suggest UD's potential to treat AR symptoms by inhibiting these targets. Notably, alpha-tocotrienol emerges as a promising multi-target inhibitor. Further in vivo and in vitro studies are needed for validation. [ABSTRACT FROM AUTHOR]

Background: Cucurbitacins are present in some common vegetables as secondary metabolites and are used by the plants against harmful microbes. Exploration of this capability of natural product based substances against wide variety of microbes seems relevant due to the ease of availability of the resources and safety. In this regard, considering the current pandemic, the antiviral properties of these molecules with a subset of Cucurbitacin I structural derivatives have been screened. The inhibition potential of the phytochemicals was assessed by the stability of the protein–ligand complex formed with the nucleocapsid protein (PDB ID: 7CDZ) of SARS-CoV-2 by computational methods. The proposition of an alternate antiviral candidate that is cost-effective and efficient relative to existing formulations is the main objective of this work. Results: Server-based molecular docking experiments revealed CBN19 (PubChem CID: 125125068) as a hit candidate among 101 test compounds, a reference molecule (K31), and 5 FDA-approved drugs in terms of binding affinities sorted out based on total energies. The molecular dynamics simulations (MDS) showed moderate stability of the protein-CBN19 complex as implied by various geometrical parameters RMSD, Rg, RMSF, SASA and hydrogen bond count. The ligand RMSD of 3.0 ± 0.5 Å, RMSF of Cα of protein with less than 5 Å, and smooth nature of SASA and Rg curves were calculated for the adduct. The binding free energy (− 47.19 ± 6.24 kcal/mol) extracted from the MDS trajectory using the MMGBSA method indicated spontaneity of the reaction between CBN19 and the protein. The multiple ADMET studies of the phytochemicals predicted some drug-like properties with minimal toxicity that mandate experimental verification. Conclusions: Based on all the preliminary in silico results, Cucurbitacin, CBN19 could be proposed as a potential inhibitor of nucleocapsid protein theoretically capable of curing the disease. The proposed molecule is recommended for further in vitro and in vivo trials in the quest to develop effective and alternate therapeutics from plant-based resources against COVID-19. [ABSTRACT FROM AUTHOR]

Oncology research progresses, yet cancer remains the largest medical need. The use of a medication with an accessible lead molecule shows great potential for long-term cancer therapy. It may help target cancer therapy and drug resistance. This work uses FDA-approved, clinically proven compounds to build novel cancer therapeutic ligands to prevent treatment resistance. Based on the reported findings, an in-silico docking experiment was performed using FDA-licensed fungus medication posaconazole. The ALK TK pdb:4cmu ligand and posaconazole docked similarly in the research. Posaconazole’s in silico docking findings were then tested against A549 lung cancer cells. Posaconazole, the lead, underwent an ADME investigation. Given in silico and experimental confirmation, acetyl, benzyl, and benzoyl derivatives of the lead molecule posaconazole was synthesized. IR, mass, 1H NMR, 13C NMR, and elemental analysis were performed on the synthesized compounds. Next, the three variants were evaluated against A549 lung cancer cells. They were then examined by utilizing computational approaches such as molecular docking, DFT analysis, MD simulation, and MMGBSA analysis. The ADME studies were conducted on posaconazole and its derivatives based on the in-vitro cell line investigation. Based on the results of an ADME study, two new ALK TK inhibitors that don’t work as Pgp substrates are good lead candidates. Thus, the present investigation fruitfully reported two lead drug candidates against the issue of resistance in cancer therapy [ABSTRACT FROM AUTHOR]

The enzyme Heme O Synthase (HOS) is essential for producing heme A and heme O, which are critical for defense against reactive oxygen species, drug detoxification, gas synthesis, transport, and electron transport in Plasmodium species. It has become vital to discover inhibitory molecules/compounds/medicines that target the synthesis of heme due to the emergence of drug‐resistant strains of Plasmodium falciparum. Therefore, in this study, we employed molecular mechanics with Generalized Born surface area (MMGBSA) calculations and docking studies to investigate potential antimalarial compounds targeting HOS from antimalarial botanicals. Screening these compounds, we have identified 2 compounds; Meliantrol and Tamarixetin with better binding affinities (−8.4 Kcal/mol and −8.3 Kcal/mol respectively) than the current standard inhibitor(Inabenfide) of HOS (−8.0 Kcal/mol). The MMGBSA calculations provided insight into the thermodynamics of the binding process and helped identify key interactions responsible for the stability of the HOS‐ligand complex. In addition, the 2 compounds were further screened comparatively with the standard HOS inhibitor considering their protein‐ligand interaction profile and ADMET profile and these 2 selected compounds outperformed Inabenfide. Our results predict that these compounds are potential drug candidates with domiciled therapeutic functions against Malaria therefore, open doors for more experimental validations for drug development. [ABSTRACT FROM AUTHOR]

Objective: This study aims to find the most promising Ganoderma lucidium targeting LRRK2 involved in PD. Methods: First ADMET analysis was performed for five compounds followed by molecular docking of each compound. Then, we perform molecular dynamics simulation of all five compounds and finally MMGBSA of all five compounds. Results: Based on molecular dynamics and MMGBSA result we reach the conclusion that Ganoderic Acid A (GAA) is the most promising compound targeting LRRK2. Therefore, GAA needs further validation through in vitro and in vivo studies. Conclusion: Ganoderma lucidum exhibits cytotoxic, hepatoprotective, antioxidative, anticancer, and antinociceptive activities. This study predicted that Ganoderma lucidum could even be used to treat neurological disorders like PD. This study suggest that the best‐identified molecule against LRRK2 is GAA and it needs rigorous in vitro and in vivo validations. [ABSTRACT FROM AUTHOR]

Objective: Alzheimer's disease (AD) is one of the most prevalent neurological ailments, affecting around 50 million individuals globally. The condition is characterized by nerve cell damage due to the formation of amyloid‐beta plaques and neurofibrillary tangles. Only a few US Food and Drug Administration (FDA)‐approved medications are available in the market which are devoid of side effects, thus, making it imperative to investigate new alternatives for countering this disease. According to a recent study, microtubule affinity regulation kinase 4 (MARK4) is attributed as one of the most promising drug targets for AD, thus, being selected for this study. Compounds from Ganoderma lucidum (Reishi mushroom) extracts were selected to be used as ligands for this study. Methods: In this study, the five most potent compounds from Ganoderma lucidum were selected and their absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis was performed, followed by molecular docking, and molecular dynamics simulation of each compound with MARK4 and supported by molecular mechanics generalized born surface area (MMGBSA) binding free energy calculations. Results: The promising compounds were selected based on their ADMET profile and interactions with the active site residues of MARK4. Based on docking scores of −9.1 and −10.3 kcal/ mol, respectively, stability assessment by molecular dynamics simulation, and MMGBSA calculations, ganoderic acid A and ganoderenic acid B were found to be the most promising compounds against MARK4 which will require further in vitro and in vivo validations. Conclusion: Through this study, it is suggested that ganoderic acid A and ganoderenic acid B might be a class of promising compounds against AD, based on computational research, and can be further studied for preclinical and clinical studies. [ABSTRACT FROM AUTHOR]

Mutations in P53 cause a loop unfolding, resulting in loss of activity and finally leading to cancer. One strategically reported way to arrest such oncogenesis is the restoration of tertiary structure as well as the function of mutant P53. In this attempt, we have designed a benzo-pyrazole-based novel ligand starting from a carbazole compound (EYB or PK9324) reported earlier to reinstate such function in mutant P53 (Y220C mutant, PDB: 6GGD). Assuming PK9324 as the template scaffold, de novo technique (Genetic algorithm, eLEA3D) was adopted within the binding pocket of 6GGD and our ligand DLIG1 was designed after several rounds of mutations. Docking and molecular dynamics (MD) simulation revealed significant interactions with key amino acid residues such as Cys220, Asp228, Leu145, Trp146, Val147, Thr150, Pro151, Pro152, Pro222, Pro223, Asp228, and Thr230. Along with sufficient binding stability, the MMGBSA analysis revealed its comparable binding free energy with other reported reference ligands (i.e. PK9324 and PK9318). Similar to these reference ligands, DLIG1 exhibited specificity in binding towards the Y220C mutant rather than towards wild-type P53. Finally, DLIG1 displayed a reorientation of a hydrophobic cavity in Y220C that hinted restoration of electrostatic interactions within the key loops of P53 favoring regain of its function. [ABSTRACT FROM AUTHOR]

The pandemic outbreak of human coronavirus is a global health concern that affects people of all ages and genders, but there is currently still no effective, approved and potential drug against human coronavirus, as many other coronavirus vaccines have serious side effects while the development of small antiviral inhibitors has gained tremendous attention. For this research, HE was used as a therapeutic target, as the spike protein displays a high binding affinity for both host ACE2 and viral HE glycoprotein. Molecular docking, pharmacophore modelling and virtual screening of 38,000 natural compounds were employed to find out the best natural inhibitor against human coronaviruses with more efficiency and fewer side effects and further evaluated via MD simulation, PCA, DCCR and MMGBSA. The lead compound 'Calceolarioside B' was identified on the basis of pharmacophoric features which depict favorable binding (ΔGbind −37.6799 kcal/mol) with the HE(5N11) receptor that describes positive correlation movements in active site residues with better stability, a robust H-bond network, compactness and reliable ADMET properties. The Fraxinus sieboldiana Blume plant containing the Calceolarioside B compound could be used as a potential inhibitor that shows a higher efficacy and potency with fewer side effects. This research work will aid investigators in the testing and identification of chemicals that are effective and useful against human coronavirus. [ABSTRACT FROM AUTHOR]

Vernonia amygdalina, a widely consumed West African food herb, can be a boon in the discovery of safe anti-obesity agents given the extensive reports on its anti-obesity and antidiabetic potentials. The main aim of this study was to screen 78 Vernonia—Derived Phytocompounds (VDPs) against the active site regions of Human Pancreatic Lipase (HPL), Human Pancreatic Amylase and Human Glucosidase (HG) as drug targets associated with obesity in silico. Structure-based virtual screening helped to identify Luteolin 7-O-glucuronoside and Andrographidoid D2 as hit compounds with dual targeting tendency towards the HPL and HG. Analysis of the molecular dynamic simulation trajectory files of the ligand-receptor complexes as computed from the thermodynamic parameters plots showed not only increased flexibility and greater interaction potential of the active site residues of the receptor towards the VDPs as indicated by the root mean square fluctuation but also higher stability as indicated by the root mean square deviation, radius of gyration and number of hydrogen bonds. The cluster analysis further showed that the interactions with important residues were preserved in the dynamic environment. These observations were further verified from Molecular Mechanics Generalized Born Surface Area Analysis, which also showed that residual contributions to the binding free energies were mainly from catalytic residues at the active sites of the enzymes. The hit compounds also feature desirable physicochemical properties and drug-likeness. This study provides in silico evidence for the inhibitory potential of phytochemicals from Vernonia amygdalina against two target enzymes in obesity. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic, caused by SARS-CoV-2, emerges as a global health problem, as the viral genome is evolving rapidly to form several variants. Advancement and progress in the development of effective vaccines and neutralizing monoclonal antibodies are promising to combat viral infections. In the current scenario, several lineages containing "co-mutations" in the receptor-binding domain (RBD) region of the spike (S) protein are imposing new challenges. Co-occurrence of some co-mutations includes delta (L452R/T478K), kappa (L452R/E484Q), and a common mutation in both beta and gamma variants (E484K/N501Y). The effect of co-mutants (L452R/E484Q) on human angiotensin-converting enzyme 2 (hACE2) binding has already been elucidated. Here, for the first time, we investigated the role of these RBD co-mutations (L452R/E484Q) on the binding affinity of mAbs by adopting molecular dynamics (MD) simulation and free-energy binding estimation. The results obtained from our study suggest that the structural and dynamic changes introduced by these co-mutations reduce the binding affinity of the viral S protein to monoclonal antibodies (mAbs). The structural changes imposed by L452R create a charged patch near the interfacial surface that alters the affinity towards mAbs. In E484Q mutation, polar negatively charged E484 helps in the formation of electrostatic interaction, while the neutrally charged Q residue affects the interaction by forming repulsive forces. MD simulations along with molecular mechanics-generalized Born surface area (MMGBSA) studies revealed that the REGN 10933, BD-368-2, and S2M11 complexes have reduced binding affinity towards the double-mutant RBD. This indicates that their mutant (MT) structures have a stronger ability to escape from most antibodies than the wild type (WT). However, EY6A Ab showed higher affinity towards the double MT-RBD complex as compared to the WT. However, no significant effect of the per-residue contribution of double-mutated residues was observed, as this mAb does not interact with the region harboring L452 and E484 residues. [ABSTRACT FROM AUTHOR]

CB2R are fascinating targets for neuropathic pain and mood disorders because of their improved biological characteristics. Experimental data on 1296 cannabinoid-2 receptor inhibitors with different structural properties were used to develop a QSAR model following OECD guidelines. This study selected the best-predicted model (80:20 splitting ratio) with fitting parameters, such as R2:0.78; F:623.6, Internal validation parameters, such as Q2Loo:0.78; CCCcv: 0.87 and external validation parameters, such as R2ext:0.77; Q2F1:0.7730; Q2F2:0.7730; Q2F3:0.76; CCCext:0.87. Following this, another QSAR model was developed by using a 50:50 split ratio for thetraining and the prediction sets, which were then swapped to evaluate the robustness of the built QSAR model by the 50:50 ratio, which also gives a deeper understanding of the chemical space. In addition, we have confirmed the QSAR result with pharmacophore modelling, and supported by molecular docking, MD simulation, MMGBSA and ADME studies. Thus, this work may enable cannabinoid 2 receptor inhibsitor development. [ABSTRACT FROM AUTHOR]

The heterodimeric complex between retinoic X receptor alpha (RXRα) and peroxisome proliferator-activated receptor gamma (PPARγ) is one of the most important and predominant regulatory systems, controlling lipid metabolism by binding to specific DNA promoter regions. X-ray and molecular dynamics (MD) simulations have revealed the average conformation adopted by the RXRα-PPARγ heterodimer bound to DNA, providing information about how multiple domains communicate to regulate receptor properties. However, knowledge of the energetic basis of the protein-ligand and protein-protein interactions is still lacking. Here we explore the structural and energetic mechanism of RXRα-PPARγ heterodimer bound or unbound to DNA and forming complex with co-crystallized ligands (rosiglitazone and 9-cis-retinoic acid) through microsecond MD simulations, molecular mechanics generalized Born surface area binding free energy calculations, principal component analysis, the free energy landscape, and correlated motion analysis. Our results suggest that DNA binding alters correlated motions and conformational mobility within RXRα–PPARγ system that impact the dimerization and the binding affinity on both receptors. Intradomain correlated motions denotes a stronger correlation map for RXRα-PPARγ-DNA than RXRα-PPARγ, involving residues at the ligand binding site. In addition, our results also corroborated the greater role of PPARγ in regulation of the free and bound DNA state. [ABSTRACT FROM AUTHOR]

Hypertension has been a significant cause of death due to elevated blood pressure worldwide. The results of molecular docking showed out of selected 40 compounds, chasmanthin (-11.05 kcal/mol), and palmarin (-11.22 kcal/mol) showed strong binding with angiotensin-converting enzyme (ACE) target. The inhibitory action of the selected phytocompounds for ACE protein was also validated by comparing it with the reference drugs, lisinopril (-9.42 kcal/mol), and enalapril (-5.07 kcal/mol). MD simulations study of 100 ns also demonstrated stability of chasmanthin, and palmarin within the active sites of ACE protein. Molecular mechanics generalised born surface area (MMGBSA) analysis of MD trajectories exhibited significant binding of palmarin with ACE (dG Bind= −38.65 ± 2.59 kcal/mol) and chasmanthin (dG Bind= −37.64 ± 2.67 kcal/mol). Drug likeness and pharmacokinetics properties of palmarin and chasmanthin was also found to be permissible, thereby suggesting the use of chasmanthin and palmarin as a novel target inhibitor against ACE protein to combat hypertension. [ABSTRACT FROM AUTHOR]

Poly [adenosine diphosphate (ADP)-ribose] polymerases (PARPs) are members of a family of 17 enzymes that performs several fundamental cellular processes. Aberrant activity (mutation) in PARP12 has been linked to various diseases including inflammation, cardiovascular disease, and cancer. Herein, a large library of compounds (ZINC-FDA database) has been screened virtually to identify potential PARP12 inhibitor(s). The best compounds were selected on the basis of binding affinity scores and poses. Molecular dynamics (MD) simulation and binding free energy calculation (MMGBSA) were carried out to delineate the stability and dynamics of the resulting complexes. To this end, root means deviations, relative fluctuation, atomic gyration, compactness, covariance, residue-residue contact map, and free energy landscapes were studied. These studies have revealed that compounds ZINC03830332, ZINC03830554, and ZINC03831186 are promising agents against mutated PARP12. [ABSTRACT FROM AUTHOR]

ALK tyrosine kinase ALK TK is an important target in the development of anticancer drugs. In the present work, we have performed a QSAR analysis on a dataset of 224 molecules in order to quickly predict anticancer activity on query compounds. Double cross validation assigns an upward plunge to the genetic algorithm–multi linear regression (GA-MLR) based on robust univariate and multivariate QSAR models with high statistical performance reflected in various parameters like, fitting parameters; R2 = 0.69–0.87, F = 403.46–292.11, etc., internal validation parameters; Q2LOO = 0.69–0.86, Q2LMO = 0.69–0.86, CCCcv = 0.82–0.93, etc., or external validation parameters Q2F1 = 0.64–0.82, Q2F2 = 0.63–0.82, Q2F3 = 0.65–0.81, R2ext = 0.65–0.83 including RMSEtr < RMSEcv. The present QSAR evaluation successfully identified certain distinct structural features responsible for ALK TK inhibitory potency, such as planar Nitrogen within four bonds from the Nitrogen atom, Fluorine atom within five bonds beside the non-ring Oxygen atom, lipophilic atoms within two bonds from the ring Carbon atoms. Molecular docking, MD simulation, and MMGBSA computation results are in consensus with and complementary to the QSAR evaluations. As a result, the current study assists medicinal chemists in prioritizing compounds for experimental detection of anticancer activity, as well as their optimization towards more potent ALK tyrosine kinase inhibitor. [ABSTRACT FROM AUTHOR]

Naltrexone is a potent opioid antagonist with good blood–brain barrier permeability, targeting different endogenous opioid receptors, particularly the mu-opioid receptor (MOR). Therefore, it represents a promising candidate for drug development against drug addiction. However, the details of the molecular interactions of naltrexone and its derivatives with MOR are not fully understood, hindering ligand-based drug discovery. In the present study, taking advantage of the high-resolution X-ray crystal structure of the murine MOR (mMOR), we constructed a homology model of the human MOR (hMOR). A solvated phospholipid bilayer was built around the hMOR and submitted to microsecond (µs) molecular dynamics (MD) simulations to obtain an optimized hMOR model. Naltrexone and its derivatives were docked into the optimized hMOR model and submitted to µs MD simulations in an aqueous membrane system. The MD simulation results were submitted to the molecular mechanics–generalized Born surface area (MMGBSA) binding free energy calculations and principal component analysis. Our results revealed that naltrexone and its derivatives showed differences in protein–ligand interactions; however, they shared contacts with residues at TM2, TM3, H6, and TM7. The binding free energy and principal component analysis revealed the structural and energetic effects responsible for the higher potency of naltrexone compared to its derivatives. [ABSTRACT FROM AUTHOR]

Using 84 structurally diverse and experimentally validated LSD1/KDM1A inhibitors, quantitative structure–activity relationship (QSAR) models were built by OECD requirements. In the QSAR analysis, certainly significant and understated pharmacophoric features were identified as critical for LSD1 inhibition, such as a ring Carbon atom with exactly six bonds from a Nitrogen atom, partial charges of lipophilic atoms within eight bonds from a ring Sulphur atom, a non-ring Oxygen atom exactly nine bonds from the amide Nitrogen, etc. The genetic algorithm–multi-linear regression (GA-MLR) and double cross-validation criteria were used to create robust QSAR models with high predictability. In this study, two QSAR models were developed, with fitting parameters like R2 = 0.83–0.81, F = 61.22–67.96, internal validation parameters such as Q2LOO = 0.79–0.77, Q2LMO = 0.78–0.76, CCCcv = 0.89–0.88, and external validation parameters such as, R2ext = 0.82 and CCCex = 0.90. In terms of mechanistic interpretation and statistical analysis, both QSAR models are well-balanced. Furthermore, utilizing the pharmacophoric features revealed by QSAR modelling, molecular docking experiments corroborated with the most active compound's binding to the LSD1 receptor. The docking results are then refined using Molecular dynamic simulation and MMGBSA analysis. As a consequence, the findings of the study can be used to produce LSD1/KDM1A inhibitors as anticancer leads. [ABSTRACT FROM AUTHOR]

Background. Dengue and Zika are two major vector-borne diseases. Dengue causes up to 25,000 deaths and nearly a 100 million cases worldwide per year, while the incidence of Zika has increased in recent years. Although Zika has been associated to fetal microcephaly and Guillain-Barré syndrome both it and dengue have common clinical symptoms such as severe headache, retroocular pain, muscle and join pain, nausea, vomiting, and rash. Currently, vaccines have been designed and antivirals have been identified for these diseases but there still need for more options for treatment. Our group previously obtained some fractions from medicinal plants that blocked dengue virus (DENV) infection in vitro. In the present work, we explored the possible targets by molecular docking a group of molecules contained in the plant fractions against DENV and Zika virus (ZIKV) NS3-helicase (NS3-hel) and NS3-protease (NS3-pro) structures. Finally, the best ligands were evaluated by molecular dynamic simulations. Methods. To establish if these molecules could act as wide spectrum inhibitors, we used structures from four DENV serotypes and from ZIKV. ADFR 1.2 rc1 software was used for docking analysis; subsequently molecular dynamics analysis was carried out using AMBER20. Results. Docking suggested that 3,5-dicaffeoylquinic acid (DCA01), quercetin 3-rutinoside (QNR05) and quercetin 3,7-diglucoside (QND10) can tightly bind to both NS3-hel and NS3-pro. However, after a molecular dynamics analysis, tight binding was not maintained for NS3-hel. In contrast, NS3-pro from two dengue serotypes, DENV3 and DENV4, retained both QNR05 and QND10 which converged near the catalytic site. After the molecular dynamics analysis, both ligands presented a stable trajectory over time, in contrast to DCA01. These findings allowed us to work on the design of a molecule called MOD10, using the QND10 skeleton to improve the interaction in the active site of the NS3-pro domain, which was verified through molecular dynamics simulation, turning out to be better than QNR05 and QND10, both in interaction and in the trajectory. Discussion. Our results suggests that NS3-hel RNA empty binding site is not a good target for drug design as the binding site located through docking is too big. However, our results indicate that QNR05 and QND10 could block NS3-pro activity inDENVand ZIKV. In the interaction with these molecules, the sub-pocket-2 remained unoccupied in NS3-pro, leaving opportunity for improvement and drug design using the quercetin scaffold. The analysis of the NS3-pro in complex with MOD10 show a molecule that exerts contact with sub-pockets S1, S1', S2 and S3, increasing its affinity and apparent stability on NS3-pro. [ABSTRACT FROM AUTHOR]

SARS-CoV-2, the virus that caused the widespread COVID-19 pandemic, is homologous to SARS-CoV. It would be ideal to develop antivirals effective against SARS-CoV-2. In this study, we chose one therapeutic target known as the main protease (Mpro) of SARS-CoV-2. A crystal structure (Id: 6LU7) from the protein data bank (PDB) was used to accomplish the screening and docking studies. A set of phytocompounds was used for the docking investigation. The nature of the interaction and the interacting residues indicated the molecular properties that are essential for significant affinity. Six compounds were selected, based on the docking as well as the MM-GBSA score. Pentagalloylglucose, Shephagenin, Isoacteoside, Isoquercitrin, Kappa-Carrageenan, and Dolabellin are the six compounds with the lowest binding energies (−12 to −8 kcal/mol) and show significant interactions with the target Mpro protein. The MMGBSA scores of these compounds are highly promising, and they should be investigated to determine their potential as Mpro inhibitors, beneficial for COVID-19 treatment. In this study, we highlight the crucial role of in silico technologies in the search for novel therapeutic components. Computational biology, combined with structural biology, makes drug discovery studies more rigorous and reliable, and it creates a scenario where researchers can use existing drug components to discover new roles as modulators or inhibitors for various therapeutic targets. This study demonstrated that computational analyses can yield promising findings in the search for potential drug components. This work demonstrated the significance of increasing in silico and wetlab research to generate improved structure-based medicines. [ABSTRACT FROM AUTHOR]

Phosphatidylinositol 3-kinase (PI3K) is a key regulatory kinase in the PI3K/AKT/mTOR signaling pathway, which is involved in the regulation of cell proliferation, differentiation, apoptosis, and angiogenesis. Class IA PI3K isoforms γ and δ share a highly homologous ATP binding site and are distinguished by only a few residues around the binding site. Subtype-selective inhibitors have been proven to have great advantages in tumor treatment. Preliminary studies have obtained PI3K inhibitors bearing a benzimidazole structural motif with a certain selectivity for PI3Kδ and PI3Kγ subtypes. On this basis, we investigated the selective inhibitory mechanism of PI3Kδ and PI3Kγ using four developed inhibitors via molecular docking, molecular dynamics, binding free energy calculations, and residue energy decomposition. This study could provide references for the further development of PI3K-isoform-selective inhibitors. [ABSTRACT FROM AUTHOR]

Lipases from Pseudomonas species are particularly useful due to their broader biocatalytic applications and temperature activity. In this study, we amplified the gene encoding wild-type cold-active lipase from the genome of psychrotrophic bacterium isolated from the Himalayan glacier. The isolated CRBC14 strain was identified as Pseudomonas sp. based on the 16S rRNA gene sequence. Lipase activity was determined by observing the hydrolysis zone on nutrient agar containing tributyrin (1%, v/v). The sequence analysis of cold-active lipase revealed a protein of 611 amino acids with a calculated molecular mass of 63.71 kDa. The three-dimensional structure of this lipase was generated through template-supported modeling. Distinct techniques stamped the model quality, following which the binding free energies of tributyrin and oleic acid in the complex state with this enzymatic protein were predicted through molecular mechanics generalized born surface area (MMGBSA). A relative comparison of binding free energy values of these substrates indicated tributyrin's comparatively higher binding propensity towards the lipase. Using molecular docking, we evaluated the binding activity of cold-active lipase against tributyrin and oleic acid. Our docking analysis revealed that the lipase had a higher affinity for tributyrin than oleic acid, as evidenced by our measurement of the hydrolysis zone on two media plates. This study will help to understand the bacterial diversity of unexplored Himalayan glaciers and the possible application of their cold-adapted enzymes. [ABSTRACT FROM AUTHOR]

The development of approaches for predictive calculation of hybridization properties of various nucleic acid (NA) derivatives is the basis for the rational design of the NA-based constructs. Modern advances in computer modeling methods provide the feasibility of these calculations. We have analyzed the possibility of calculating the energy of DNA/RNA and RNA/RNA duplex formation using representative sets of complexes (65 and 75 complexes, respectively). We used the classical molecular dynamics (MD) method, the MMPBSA or MMGBSA approaches to calculate the enthalpy (ΔH°) component, and the quasi-harmonic approximation (Q-Harm) or the normal mode analysis (NMA) methods to calculate the entropy (ΔS°) contribution to the Gibbs energy () of the NA complex formation. We have found that the MMGBSA method in the analysis of the MD trajectory of only the NA duplex and the empirical linear approximation allow calculation of the enthalpy of formation of the DNA, RNA, and hybrid duplexes of various lengths and GC content with an accuracy of 8.6%. Within each type of complex, the combination of rather efficient MMGBSA and Q-Harm approaches being applied to the trajectory of only the bimolecular complex makes it possible to calculate the of the duplex formation with an error value of 10%. The high accuracy of predictive calculation for different types of natural complexes (DNA/RNA, DNA/RNA, and RNA/RNA) indicates the possibility of extending the considered approach to analogs and derivatives of nucleic acids, which gives a fundamental opportunity in the future to perform rational design of new types of NA-targeted sequence-specific compounds. [ABSTRACT FROM AUTHOR]

Pharmacophore modelling studies have been performed for a series of 2,4-disubstituted-pyrimidines derivatives as EGFR L858R/T790M tyrosine kinase inhibitors. The high scoring AARR.15 hypothesis was selected as the best pharmacophore model with the highest survival score of 3.436 having two hydrogen bond acceptors and two aromatic ring features. Pharmacophore-based virtual screening followed by structure-based yielded the six molecules (ZINC17013227, ZINC17013215, ZINC9573324, ZINC9573445, ZINC24023331 and ZINC17013503) from the ZINC database with significant in silico predicted activity and strong binding affinity towords the EGFR L858R/T790M tyrosine kinase. In silico toxicity and cytochrome profiling indicates that all the 06 virtually screened compounds were substrate/inhibitors of the CYP-3A4 metabolizing enzyme and were non-carcinogenic and devoid of Ames mutagenesis. Density functional theory (DFT) and molecular dynamic (MD) simulation further validated the obtained hits. [ABSTRACT FROM AUTHOR]

Experimental and theoretical studies have provided structural information regarding the shift from inactive to active EGFR, throughout which both conformations are linked via binding to specific tyrosine kinase inhibitors. For HER2, an intermediate active-inactive receptor conformation is present in the PDB, which has been co-crystallized with tak-285. The affinity of HER2 in monomeric state to tak-285 has been previously reported. However, the lack of structural knowledge of HER2 limits our capacity to understand whether tak-285, or other known HER2 inhibitors, selectively bind active, inactive, or intermediate forms of HER2. To elucidate mechanisms by which tak-285 binds to HER2, we first obtained information regarding the structural features of the active state of HER2 via microsecond MD simulations from the crystallized intermediate structure previously determined. Based on these HER2 conformers, together with the inactive HER2 conformer obtained in a previous study, we used docking and MD simulations coupled to MMGBSA approach to assess binding of tak-285 and lapatinib, known HER2/EGFR dual inhibitors, to HER2. Structural and energetic studies revealed that tak-285 binds with a greater affinity than lapatinib to active and intermediate active-inactive forms of HER2. This is in accordance with experimental findings that showed the tak-285 inhibitor has increased activity relative to lapatinib in breast cancer cell lines. [ABSTRACT FROM AUTHOR]

Since the last 4 decades, Bedaquiline has been the first drug discovered as a new kind of anti-tubercular agent and received FDA approval in December 2012 to treat pulmonary multi-drug resistance tuberculosis (MDR-TB). It demonstrates excellent efficacy against MDR-TB by effectively inhibiting mycobacterial ATP synthase. In addition to these apparent assets of Bedaquiline, potential disadvantages of Bedaquiline include inhibition of the hERG (human Ether-à-go-related gene; KCNH2), potassium channel (concurrent risk of cardiac toxicity), and risk of phospholipidosis due to its more lipophilic nature. To assist the effective treatment of MDR-TB, highly active Bedaquiline analogs that display a better safety profile are urgently needed. A structure-based virtual screening approach was used to address the toxicity problems associated with Bedaquiline. Among the virtually screened compound, CID 15947587 had significant docking affinity (− 5.636 kcal/mol) and highest binding free energy (ΔG bind − 85.2703 kcal/mol) towards the Mycobacterial ATP synthase enzyme with insignificant cardiotoxicity and lipophilicity. During MD simulation studies (50 ns), the molecule optimizes its conformation to fit better the active receptor site justifying the binding affinity. The obtained results showed that CID15947587 could be a useful template for further optimizing the MDR-TB inhibitor. [ABSTRACT FROM AUTHOR]

One in every two humans is having Helicobacter pylori (H. pylori) in stomach causing gastric ulcer. Emergence of several drugs in eliminating H. pylori has paved way for emergence of multidrug resistance in them. This resistance is thriving and thereby necessitating the need of a potent drug. Identifying a potential target for medication is crucial. Bacterial 5′-methylthioadenosine/S-enosyl homocysteine nucleosidase (MTAN) is a multifunctional enzyme that controls seven essential metabolic pathways. It functions as a catalyst in the hydrolysis of the N-ribosidic bond of adenosine-based metabolites: S-adenosylhomocysteine (SAH), 5′-methylthioadenosine (MTA), 5′-deoxyadenosine (5′-DOA), and 6-amino-6-deoxyfutalosine. H. pylori unlike other bacteria and humans utilises an alternative pathway for menaquinone synthesis. It utilises Futosiline pathway for menaquinone synthesis which are obligatory component in electron transport pathway. Therefore, the enzymes functioning in this pathway represent them-self as a point of attack for new medications. We targeted MTAN protein of H. pylori to find out a potent natural hit to inhibit its growth. A comparative analysis was made with potent H. pylori MTAN (HpMTAN) known inhibitor, 5′-butylthio-DADMe-Immucillin-A (BuT-DADMe-ImmA) and ZINC natural subset database. Optimized ligands from the ZINC natural database were virtually screened using ligand based pharmacophore hypothesis to obtain the most efficient and potent inhibitors for HpMTAN. The screened leads were evaluated for their therapeutic likeness. Furthermore, the ligands that passed the test were subjected for MM-GBSA with MTAN to reveal the essential features that contributes selectivity. The results showed that Van der Waals contributions play a central role in determining the selectivity of MTAN. Molecular dynamics (MD) studies were carried out for 100 ns to assess the stability of ligands in the active site. MD analysis showed that binding of ZINC00490333 with MTAN is stable compared to reference inhibitor molecule BuT-DADMe-ImmA. Among the natural inhibitors screened after various docking procedures ZINC00490333 has highest binding score for HpMTAN (− 13.987). The ZINC inhibitor was successful in reproducing the BuT-DADMe-ImmA interactions with HpMTAN. Hence we suggest that ZINC00490333 compound may represent as a good lead in designing novel potent inhibitors of HpMTAN. This in silico approach indicates the potential of this molecule for advancing a further step in gastric ulcer treatment. [ABSTRACT FROM AUTHOR]

Valproic acid (VPA) is a compound currently used in clinical practice for the treatment of epilepsy as well as bipolar and mood disorders. VPA targets histone deacetylases (HDACs), which participate in the removal of acetyl groups from lysine in several proteins, regulating a wide variety of functions within the organism. An imbalance or malfunction of these enzymes is associated with the development and progression of several diseases, such as cancer and neurodegenerative diseases. HDACs are divided into four classes, but VPA only targets Class I (HDAC1–3 and 8) and Class IIa (HDAC4–5, 7 and 9) HDACs; however, structural and energetic information regarding the manner by which VPA inhibits these HDACs is lacking. Here, the structural and energetic features that determine this recognition were studied using molecular docking and molecular dynamics (MD) simulation. It was found that VPA reaches the catalytic site in HDAC1–3 and 7, whereas in HDAC6, VPA only reaches the catalytic tunnel. In HDAC4, VPA was bound adjacent to L1 and L2, a zone that participates in corepressor binding, and in HDAC8, VPA was bound to the hydrophobic active site channel (HASC), in line with previous reports. [ABSTRACT FROM AUTHOR]

Kinase inhibitor selectivity is a major concern for the design of small-molecule compounds. As a member of serine/threonine protein kinase family, glycogen synthase kinase 3β (GSK3β) is involved in diverse biological processes and abnormal dysregulation of its activity has been associated with several pathologies, including type II diabetes, Alzheimer's disease, bipolar disorders, and cancers. A small-molecule PF-367 significantly inhibited the GSK3 enzymatic activity over its closest cyclin-dependent kinase 2 (CDK2) with >1000-fold selectivity. However, the PF-367 selectively binding to GSK3β over CDK2 has remained unclear. Here, molecular docking, molecular dynamics (MD) simulations, and molecular mechanics_generalized born/surface area (MM_GBSA) binding free energy calculations, as well as the decomposition of binding free energies were performed to investigate the selective binding mechanism of PF-367 to the ATP-binding site of GSK3β over CDK2. The results revealed that the exposure of the terminal triazole ring of PF-367 into the solvent environment may be responsible for the weak binding complex of CDK2−PF-367, which was further confirmed by the binding free energy calculations and the identified key residues (Phe67, Lys85, Thr138, and Arg141) contributing to the binding interaction. The obtained data can not only decipher the origin of selectivity, but also be used for the design of more potent and selective GSK3β inhibitors. [ABSTRACT FROM AUTHOR]

Half of the world population is infected by the Gram‐negative bacterium Helicobacter pylori (H. pylori). It colonizes in the stomach and is associated with severe gastric pathologies including gastric cancer and peptic ulceration. The most virulent factor of H. pylori is the cytotoxin‐associated gene A (CagA) that is injected into the host cell. CagA interacts with several host proteins and alters their function, thereby causing several diseases. The most well‐known target of CagA is the tumor suppressor protein ASPP2. The subdomain I at the N‐terminus of CagA interacts with the proline‐rich motif of ASPP2. Here, in this study, we carried out alanine scanning mutagenesis and an extensive molecular dynamics simulation summing up to 3.8 μs to find out hot spot residues and discovered some new protein‐protein interaction (PPI)‐modulating molecules. Our findings are in line with previous biochemical studies and further suggested new residues that are crucial for binding. The alanine scanning showed that mutation of Y207 and T211 residues to alanine decreased the binding affinity. Likewise, dynamics simulation and molecular mechanics with generalized Born surface area (MMGBSA) analysis also showed the importance of these two residues at the interface. A four‐feature pharmacophore model was developed based on these two residues, and top 10 molecules were filtered from ZINC, NCI, and ChEMBL databases. The good binding affinity of the CHEMBL17319 and CHEMBL1183979 molecules shows the reliability of our adopted protocol for binding hot spot residues. We believe that our study provides a new insight for using CagA as the therapeutic target for gastric cancer treatment and provides a platform for a future experimental study. [ABSTRACT FROM AUTHOR]

Cyclin‐dependent protein kinases (CDKs) are serine/threonine kinases of the CMGC family. The cyclin D/CDK4 complex plays an important role in cell proliferation. Deregulation of the CDK4‐cyclin D pathway leads to uncontrolled cell proliferation, causing various tumors and cancers in humans. CDK4 overexpression is widely observed in colorectal and uterine cervical carcinomas, liposarcomas, osteosarcomas, and breast cancer. CDK4 is extensively studied as a therapeutic target in breast cancer. Hence, the identification of the binding modes of inhibitors and important active‐site residues is crucial. However, an experimentally determined crystal structure of ligand‐bound CDK4 kinase has not been reported to date. Thus, this study aimed to identify hotspot residues in the ligand‐binding interface of CDK4. Three compounds exhibiting very high inhibitory activity against CDK4 (Cpd03, Cpd13, and Cpd14) were selected as potent antagonists in this study. Molecular docking and molecular dynamics simulation were carried out to identify the binding modes and crucial residues. For validation, we calculated total binding free energy and energy decomposition, which identified residues Ala151, Ala30, Asp152, His89, Ile9, Leu141, Phe87, Val17, and Val90 are the highest‐energy contributors important for inhibitor binding. The results of our study provide insights in the binding patterns of CDK4 inhibitors and reveal key residues in the ligand‐binding interface. [ABSTRACT FROM AUTHOR]

HIV-I cellular infection triggered by CD4 receptor protein and viral envelop glycoprotein gp120 binding event. CD4:gp120 surface is directed by the contact points of a hydrophobic gp120 cavity capped by Phe43CD4 and ionic bonds residues Arg59CD4 and Asp368gp120. The binding sites originated by gp120 and CD4 interaction leads to the entry of HIV-I into the host membrane, where, gp120 and a CD4 binding site becomes the main mark for plenty of drug uncovering program. Here, we took the crystal structure of small-molecule of gp120 in a complex that concurrently pursues both of the hotspots of gp120 binding sites. All ligands in our study are small molecules that are able to obstruct the protein-protein interactions between CD4 and gp120. This study aims at the thermodynamical insights of the ligand binding in CD4 binding sites using Molecular Dynamics Simulations Study and calculation of binding free energy. The physical of binding of drugs distinctly indicates a hydrophobic and electrostatics interaction motivated binding of ligands which explicitly mark CD4 binding sites. [ABSTRACT FROM AUTHOR]

The FDA approved drug suvorexant binds to the horseshoe shape pocket of OX2R with the boat conformation. The horseshoe shape pocket plays an important role on the biological activity of OX2R in the cell membrane. To study the binding mechanism between the horseshoe shape pocket of OX2R and boat conformation of suvorexant, the crystal structures of wild type and N324A mutant of OX2R in complex with antagonist suvorexant are chosen to perform molecular dynamics (MD) simulations, QM/MM, and MMGBSA calculations. By comparison with the wild type of OX2R, the results show the 1,2,3‐triazole and p‐toluamide groups of suvorexant are changed in the N324A mutant of OX2R during 200 ns MD simulations. The QM/MM and weak interaction analysis are employed to calculate the non‐covalent bonds interaction between suvorexant and key residues in the wild type and N324A mutant of OX2R. The MMGBSA calculations indicate the entropy energy is an important influence factor for suvorexant affinity in the distorted horseshoe shape pocket of OX2R. Our results not only show the horseshoe shape pocket of OX2R is the necessary conformation for the binding of antagonist suvorexant, but also give the important sites and structural features for antagonist design of OX2R. [ABSTRACT FROM AUTHOR]

The 2016 D3R Grand Challenge 2 includes both pose and affinity or ranking predictions. This article is focused exclusively on affinity predictions submitted to the D3R challenge from a collaborative effort of the modeling and informatics group. Our submissions include ranking of 102 ligands covering 4 different chemotypes against the FXR ligand binding domain structure, and the relative binding affinity predictions of the two designated free energy subsets of 15 and 18 compounds. Using all the complex structures prepared in the same way allowed us to cover many types of workflows and compare their performances effectively. We evaluated typical workflows used in our daily structure-based design modeling support, which include docking scores, force field-based scores, QM/MM, MMGBSA, MD-MMGBSA, and MacroModel interaction energy estimations. The best performing methods for the two free energy subsets are discussed. Our results suggest that affinity ranking still remains very challenging; that the knowledge of more structural information does not necessarily yield more accurate predictions; and that visual inspection and human intervention are considerably important for ranking. Knowledge of the mode of action and protein flexibility along with visualization tools that depict polar and hydrophobic maps are very useful for visual inspection. QM/MM-based workflows were found to be powerful in affinity ranking and are encouraged to be applied more often. The standardized input and output enable systematic analysis and support methodology development and improvement for high level blinded predictions. [ABSTRACT FROM AUTHOR]

VEGFR-2, a transmembrane tyrosine kinase receptor is responsible for angiogenesis and has been an attractive target in treating cancers. The inhibition mechanism of structurally diverse urea derivatives, reported as VEGFR-2 inhibitors, was explored by pharmacophore modeling, QSAR, and molecular dynamics based free energy analysis.The pharmacophore hypothesis AADRR, resulted in a highly significant atom based 3D-QSAR model ( r2 = 0.94 and q2 = 0.84). Binding free energy analysis of the docked complexes of highly active and inactive compounds, after 7 ns MD simulation, revealed the importance of van der Waals interaction in VEGFR-2 inhibition. The decomposition of binding free energy on a per residue basis disclosed that the residues in hinge region and hydrophobic pocket play a role in discriminating the active and inactive inhibitors. Thus, the present study proposes a pharmacophore hypothesis representing the identified interactions pattern and its further application as a template in screening databases to identify novel VEGFR-2 inhibitor scaffolds. [ABSTRACT FROM AUTHOR]

Binding estimation after refinement (BEAR) is a novel automated computational procedure suitable for correcting and overcoming limitations of docking procedures such as poor scoring function and the generation of unreasonable ligand conformations. BEAR makes use of molecular dynamics simulation followed by MM-PBSA and MM-GBSA binding free energy estimates as tools to refine and rescore the structures obtained from docking virtual screenings. As binding estimation after refinement relies on molecular dynamics, the entire procedure can be tailored to the needs of the end-user in terms of computational time and the desired accuracy of the results. In a validation test, binding estimation after refinement and rescoring resulted in a significant enrichment of known ligands among top scoring compounds compared with the original docking results. Binding estimation after refinement has direct and straightforward application in virtual screening for correcting both false-positive and false-negative hits, and should facilitate more reliable selection of biologically active molecules from compound databases. [ABSTRACT FROM AUTHOR]

In early 2020, many scientists are rushing to discover novel drugs and vaccines against the coronavirus, and treatments for COVID-19, because, Coronavirus Disease 2019 (COVID-19), a life-threatening viral disease which is caused by SARS-CoV-2, affected first in china and quickly spread throughout the world. According to the WHO data, as on May 2020, there are more than 60 lakhs peoples in the world affected by COVID19, out of these more than 3.7 lakhs peoples are died. So in this emergency situation, it is very difficult to discover novel drugs with all clinical trials and also determine the side effects, adverse effects etc. So, It is important to treat with some natural remedies which are using regularly in our diet like Curcuma longa (Turmeric)for COVID19. In this article, in-silico studies have been performed to explore the binding modes of chemical constituents for natural remedies like Curcuma longa (Turmeric)against COVID19 main protease (PDB id - 5R82) targeting corona virususing Schrodinger suit 2019-4. The molecular docking studies are performed by Glide module, in-silico ADMET screening was performed by qik prop module and, binding energy of ligands was calculated using PRIME MMGB/SA module. The chemical constituents from turmeric like Cyclocurcumin, Curcumin are significantly active against COVID19 with Glide score more than -6 when compared to currently used drug Hydroxychloroquine (-5.47). The docking results of the compounds exhibited similar mode of interactions with COVID19 and the residues THR24, THR25, THR26, LEU27, SER46, MET49, HIE41, GLN189, ARG188, ASP187, MET165, HIE164, PHE181 and THR54 play a crucial role in binding with ligands. In conclusion, the chemical constituents from turmeric like Cyclocurcumin, Curcumin are significantly active against COVID19 and used for further development. [ABSTRACT FROM AUTHOR]

In early 2020, many scientists are rushing to discover novel drugs and vaccines against the coronavirus, and treatments for COVID-19, because, Coronavirus Disease 2019 (COVID-19), a life-threatening viral disease which is caused by SARS-CoV2, affected first in china and quickly spread throughout the world. According to the WHO data, as on May 2020, there are more than 60 lakhs peoples in the world affected by COVID19, out of these more than 3.7 lakhs peoples are died. So in this emergency situation, it is very difficult to discover novel drugs with all clinical trials and also determine the side effects, adverse effects etc. So, It is important to treat with some natural remedies which are using regularly in our diet like Curcuma longa (Turmeric)for COVID19. In this article, in-silico studies have been performed to explore the binding modes of chemical constituents for natural remedies like Curcuma longa (Turmeric)against COVID19 main protease (PDB id - 5R82) targeting corona virususing Schrodinger suit 2019-4. The molecular docking studies are performed by Glide module, in-silico ADMET screening was performed by qik prop module and, binding energy of ligands was calculated using PRIME MMGB/SA module. The chemical constituents from turmeric like Cyclocurcumin, Curcumin are significantly active against COVID19 with Glide score more than -6 when compared to currently used drug Hydroxychloroquine (-5.47). The docking results of the compounds exhibited similar mode of interactions with COVID19 and the residues THR24, THR25, THR26, LEU27, SER46, MET49, HIE41, GLN189, ARG188, ASP187, MET165, HIE164, PHE181 and THR54 play a crucial role in binding with ligands. In conclusion, the chemical constituents from turmeric like Cyclocurcumin, Curcumin are significantly active against COVID19 and used for further development. [ABSTRACT FROM AUTHOR]

Pesticides are used extensively in agriculture, and their residues in food must be monitored to prevent toxicity. The most abundant protein in cow's milk, β-lactoglobulin (BLG), shows high affinity for diverse hydrophobic ligands in its central binding pocket, called the calyx. Several of the most frequently used pesticides are hydrophobic. To predict if BLG may be an unintended carrier for pesticides, we tested its ability to bind 555 pesticides and their isomers, for a total of 889 compounds, in a rigid docking screen. We focused on the analysis of 60 unique molecules belonging to the five pesticide classes defined by the World Health Organization, that docked into BLG's calyx with ΔGs ranging from −8.2 to −12 kcal mol−1, chosen by statistical criteria. These "potential ligands" were further analyzed using molecular dynamic simulations, and the binding energies were explored with Molecular Mechanics/Generalized Born/Surface Area (MMGBSA). Hydrophobic pyrethroid insecticides, like cypermethrin, were found to bind as deeply and tightly into the calyx as BLG's natural ligand, palmitate; while polar compounds, like paraquat, were expelled. Our results suggest that BLG could be a carrier for pesticides, in particular for pyrethroid insecticides, allowing for their accumulation in cow's milk beyond their solubility restrictions. This analysis opens possibilities for pesticide biosensor design based on BLG. [ABSTRACT FROM AUTHOR]