Schrodinger Suite Research Articles

In silico evaluations of phytochemicals from Withania somnifera exhibiting anticancer activity against NAD[P]H-quinone oxidoreductase.

Cancer is a leading cause of death globally and in the US, prompting research into medicinal plants with anticancer properties. Withania somnifera, or Ashwagandha, is one such plants, known for its diverse pharmacological effects. Withaferin A and Viscosalactone B are two compounds found in Ashwagandha with known anticancer activity. The protein NQO1, overexpressed in various cancers, was the focus of this study. We hypothesize that specific phytochemicals in Withania somnifera can effectively interact with and inhibit the NQO1 protein, thereby exhibiting anticancer properties. This study aims to identify these interactions using in silico approaches. CFDT was performed using the Gaussian 16 program package, followed by QSAR analysis of the compounds in the PASS online web server. The Schrodinger suite was used to carry out ligand and protein preparation, molecular docking, and molecular dynamic simulation to analyse the interaction of these compounds with NQO1 and ADME studies. Protox-II and SWISSADME tools were used to predict the toxicity and blood-brain barrier permeability of the phytochemicals. CDFT and frontier molecular orbital analyses predicted the stability and reactivity of all the selected molecules. QSAR analysis predicted the biological activity and toxicity of the compounds. Withaferin A exhibited the highest glide gscore (-4.953kcal/mol) and demonstrated 6 hydrogen bond interactions with NQO1, suggesting its potential as an anticancer agent. Conceptual density functional theory-based analysis suggested the strong electrophilicity of the ligands, further supporting their potential anticancer activities. Viscosalactone B, another phytochemical from Ashwagandha, also showed interactions involving 6 hydrogen bonds with NQO1, with a glide gscore of (-4.593kcal/mol). Molecular dynamic simulations validated the stability of the Withaferin A-NQO1 complex. ADME-T properties predicted high oral absorption for the selected ligands, indicating that Withaferin A could be a viable orally administered drug.

Investigation of Cnidium monnieri compounds as phosphodiesterase-5 antagonists in erectile dysfunction via molecular docking and dynamic simulation

This study aimed at evaluating the inhibitory potential of bioactive compounds from C. monnieri and predicting lead compounds for achieving and maintaining penile erection through computational models. A total of 79 compounds were retrieved for the plant through public repositories, phosphodiesterase-5 (PDE-5) was retrieved from the data bank for proteins (PDB). The molecular docking, free binding energy calculation, pharmacophore modeling and molecular dynamic simulation were performed using Schrodinger suite (2017–1). The quantum chemical calculation was also carried out with Spartan 14 computational software. Among the 79 compounds virtually screened against Phosphodiesterase-5 (PDE-5), eight (8) bioactive compounds showed potent antagonist against PDE-5 with varying binding scores comparable to that of Sildenafil (co-crystalized ligand). Monnieriside (−10.625 kcal/mol), Diosmetin (−10.041 kcal/mol and Isogosferol (−10.038 kcal/mol) were observed to have the best docking score comparable with Sildenafil (−11.872 kcal/mol). The fitness score range of 0.982–1.941 confirmed the validation of the docking scores using e-pharmacophore hypothesis. The result of the MD simulation reveals better stability of hit compound-protein complex (Monnieriside A-PDE-5) compared with the Sildenafil-PDE-5 complex. None of the hit compounds violated more than one rule of five and within the reference range for pharmacokinetics parameters. The quantum mechanics estimation revealed the hit molecules possess proton accepting and donating potential therefore, possess antagonistic potential. Based on the results from this study, the three top binding compounds may be predicted as potent inhibitors of PDE-5 and could use as lead compound for discovery of potent drugs for erectile dysfunction.

NOVEL IMIDAZOLE CONTAINING CHALCONE DERIVATIVES AS AN AROMATASE INHIBITOR: SYNTHESIS, DOCKING STUDIES, BIOLOGICAL SCREENING AND ADME STUDIES

Chalcone derivatives have been proven and documented as non-steroidal anticancer agents. A study of chalcone can be performed as an aromatase inhibitor. One crucial strategy for managing estrogen-positive breast cancer is aromatase inhibition. A total of 13 derivatives of chalcone were synthesized by the aldol condensation reaction and characterized by FTIR, MS, and NMR. Molecular docking was performed by the maestro Schrodinger Suite. In silico ADME study was executed by the QikProp software. All 13 compounds were assessed for the cytotoxicity study in human cancer cell line MCF-7 and are subject to further aromatase inhibition assay on selected chalcone derivatives. Four compounds, 3gA, 3jA, 3kA, and 3lA were found to be more potent chalcone derivatives with their IC50 values of 18.13±1.19 µM, 21.71±1.61 µM, 16.36±1.47 µM and 21.06±1.87 µM, respectively. Using a fluorogenic test kit, the in vitro aromatase inhibitory activity of four drugs (3gA, 3jA, 3kA, and 3lA) was investigated. The values of IC50 for compounds 3gA, 3jA, 3kA, and 3lA were found to be 2.76±0.83 µM, 6.45±3.38 µM, 4.82±1.52 µM and 3.00±1.63 µM, respectively. Lastly, QikProp 4.8 software was used to calculate the ADME parameters (absorption, distribution, metabolism, and excretion) of synthesized compounds. It was concluded that 3gA is the most potent compound having potent aromatase inhibitory activity in comparison to Letrozole with an IC50 value of 2.76±0.83 µM. At the same time, 3jA and 3lA have good aromatase inhibitory activity. Therefore, For the identification of aromatase inhibitory activity, these compounds make good lead compounds for further study as anticancer agents.

Phytochemical on-line screening and in silico study of Helianthemum confertum: antioxidant activity, DFT, MD simulation, ADME/T analysis, and xanthine oxidase binding.

Seven components from the methanol extract of the aerial part of the endemic species Helianthemum confertum were isolated and identified for the first time. Investigating this species and its separated components chemical make-up and radical scavenging capacity, was the main goal. Using an online HPLC-ABTS˙+ test, ORAC, and TEAC assays, the free radical scavenging capacity of the ethyl acetate extract was assessed. The fractionation of these extracts by CC, TLC, and reverse-phase HPLC was guided by the collected data, which was corroborated by TEAC and ORAC assays. Molecular docking studies, DFT at the B3LYP level, and an examination of the ADME/T predictions of all compounds helped to further clarify the phytochemicals' antioxidant potential. Isolation and identification of all components were confirmed through spectroscopy, which revealed a mixture (50-50%) of para-hydroxybenzoic acid 1 and methyl gallate 2, protocatechuic acid 3, astragalin 4, trans-tiliroside 5, cis-tiliroside 6, contaminated by trans-tiliroside and 3-oxo-α-ionol-β-d-glucopyranoside 7, as well as two new compounds for the genus Helianthemum (2 and 7). With a focus on compounds 1, 2, 3, and 4, the results clearly showed that the extract and the compounds tested from this species had a high antioxidant capacity. Within the xanthine oxidase enzyme's pocket, all of the components tested showed strong and stable binding. In light of these findings, the xanthine oxidase/methyl gallate 2 complex was simulated using the Desmond module of the Schrodinger suite molecular dynamics (MD) for 100 ns. Substantially stable receptor-ligand complexes were observed following 1 ns of MD simulation.

Small Molecule Inhibition of MAGE-A3 Induces Cell Cycle Arrest and Apoptosis in Multiple Myeloma

Background: The Type I Melanoma Antigen Gene-A3 (MAGE-A3) is commonly expressed in multiple myeloma (MM), a cancer of plasma cells. MAGE-A3 binds to Kap1 to form ubiquitin (Ub) ligase complexes and is associated with inhibition of apoptosis, resistance to chemotherapy, and cell cycle dysregulation. The highly conserved MAGE Homology Domain (MHD) undergoes a conformation change from “closed” to “open” in order to complex with Kap1, activate Ub ligase activity, and bind substrates. RNA interference (RNAi) knockdown of MAGE-A3 in MM cells results in upregulation of the endogenous CDK4/6 inhibitor P21 Cip1 and pro-apoptotic BIM, resulting in cell cycle arrest and intrinsic apoptosis. Knockdown of MAGE-A3 also increased cell death in response to melphalan and panobinostat, but not to bortezomib or cis-platin. These findings lead to the hypothesis that small molecule inhibition (SMI) of MAGE-A3 Ub ligase activity will have therapeutic application in this disease. Methods: We used the Schrodinger suite to perform in silico screening of a custom designed library of compounds using the crystal structure of the MAGE-A3 MHD to identify potential binding molecules that stabilize the closed MHD conformation. Candidates were then screened on human myeloma cell lines (HMCL) by CellTiter-Glo assay to identify compounds that reduced cell viability. Isothermal titration calorimetry was used to identify candidate SMI that bound to the MHD. HMCL were co-incubated with SMI; cell cycling was assessed by BrdU assay and apoptosis by Annexin V staining. Protein expression of p21 Cip1, BIM, and MAGE-A3 was assessed by Western blot. Combinatorial indexes in co-incubation experiments with ergotamine and chemotherapy agents were calculated with the Chou-Talalay method using CompuSyn. Results: Structure-based and biochemical screening nominated ergotamine as a candidate MAGE-A3 SMI. Ergotamine bound to the MAGE-A3 MHD and induced cell cycle arrest and apoptosis in MAGE-A3-expressing human myeloma and lymphoma cell lines and increased expression of pro-apoptotic BIM and p21 Cip1, similar to results with RNAi knockdown. These effects were not observed in negative control MAGE-A3(-) lymphoma cells. Co-incubation of ergotamine with chemotherapy agents melphalan or panobinostat resulted in synergistic killing of MAGE-A3+ HMCL. Ergotamine did not synergize with bortezomib or cis-platin under these conditions. Conclusions: These results support the combined structural and biochemical methods as an efficient means of screening for candidate inhibitors for MAGE-A3. Ergotamine recapitulated the results of RNAi knockdown of MAGE-A3 in cells that express the target, supporting a tool compound for further pharmacologic development. MAGE-A3 SMI have the potential to be a novel class of MM therapy that may be effective alone or in combination with chemotherapy or immune oncology agents. MAGE inhibitors may have broader application in other target-expressing cancers, including lung, melanoma, breast, and ovarian cancers, which are among the most common causes of cancer death.

Discovery of Small‐Molecule Inhibitors Targeting Progranulin‐Sortilin: An in‐silico Approach Using Molecular Docking, Molecular Dynamics Simulations, and DFT Studies

AbstractIntroduction: Reduction in progranulin (PGRN) have been associated with various neurodegenerative diseases. PGRN binds with high affinity to sortilin (SORT), a membrane transporter, resulting in its cellular uptake and eventual degradation in the lysosome. Inhibition of the SORT‐PGRN interaction has the potential to increase PGRN levels up to 2.5‐fold. Methodology: A virtual screening of curated CNS library of >47 K ligands was done with sortilin receptor (6X3L) through virtual screening workflow in Schrodinger suite. Co‐crystallised ligand was used as a positive control. Docking was done through HTVS, then SP and finally XP model followed by binding free energy calculations (MMGBSA). Based on the result analysis of molecular docking, binding free energy and interactions, docked complexes were chosen for molecular dynamics (MD) studies. DFT studies and MEP plotting were carried out for the screened ligands. Drug likeliness and ADMET studies were also carried out. Results: The virtual screening workflow yielded 139 ligands. Two test ligands and a control were selected and further evaluated through molecular dynamics studies. Both the test ligands (1625 & 127) had comparative docking score (−5.96 & −6.46 kcal/mol) as that of control ligand (−6.21 kcal/mol respectively) and but better binding free energy (−54.66, −53.12 & −43.21 kcal/mol respectively). MD simulations confirmed the docking results for all the three ligands where our test ligand 1625 reached equilibrium quickly as compared to the rest. Our test compounds also showed favourable characteristics of a CNS acting drug and favourable ADMET properties. According to DFT studies, the test ligands 127 and 1625 had FMO (HOMO‐LUMO) energy gaps of 8.86 eV and 9.83 eV, respectively, that were lesser than the control ligand (9.89 eV). Additionally, FMO energy gap of the test ligands and the control ligand were in agreement with the results of docking. MEP diagram provided the picture of electron rich, neutral and electron deficient surface of the test ligands and that of the control with respective color code red, green and blue. Conclusion: Our study results showed a promising CNS specific ligand as an inhibitor of PRGN‐SORT interactions and has a potential to be developed as a drug through in‐vitro and in‐vivo studies.

Molecular mechanics and dynamics simulation of CD-47/SIRPα blockade study: A computational study on overcoming immunotherapeutic resistance in pancreatic ductal adenocarcinoma

The sting of pancreatic ductal adenocarcinoma remains an irksome burden to the human populace. The focus of recent research has switched from finding the perfect medicinal medication to blocking immunological checkpoint proteins such as the signal regulating protein alpha-cluster of differentiation 47 (SIRPα-CD47). The search for CD47/SIRPα inhibitors with excellent oral bioavailability and permeability continues to elude researchers. This research aims to identify bioactive molecules with negligible side as inhibitor SIRPα-CD47 signaling cascade. Bioactive flavonoids from African medicinal plants were virtually screened against the SIRP-α binding site of CD47 using Schrodinger suite 2017-v1. The docking score was validated and complex stability performed using Gromacs. Among the bioactive flavonoids, five (5) compounds were predicted as potent inhibitors of CD47 with pelargonidin observed to have the best binding affinity of −6.715 kcal/mol. Validation using QSAR and pharmacophore modeling further confirm the interaction with predicted pIC50 range of 5.981 to 6.841 µM and fitness score of 1.109 to 1.530. Drug-likeness prediction revealed that all hit compounds obey Lipinski’s rule of five. The MD simulation result predicted the stability of pelargonidin and malvidin comparable to the standard drug NCGC00138783. The quantum mechanics estimation revealed that, the hit compounds have proton donating and accepting ability hence, they possess inhibitory potential. From the molecular docking, post-docking and MD simulation analyzes of this study, Pelargonidin, malvidin and Peonidin were proposed as suitable candidates that could be probed further for developing a new target-specific immunotherapeutic agent against PDAC.

In-silico screening and molecular dynamics simulation of quinazolinone derivatives as PARP1 and STAT3 dual inhibitors: a novel DML approaches

Modern cancer therapy now routinely employs the blocking of many oncoproteins or pathways. With two or more medicines, multiple inhibitions are often accomplished via DML techniques. In this study, we developed 30 quinazolinone derivatives as PARP1 and STAT3 dual inhibitors using DML methods and these compounds were tested for their dual inhibitory effect on PARP1 and STAT3 using docking, MM-GBSA, and molecular dynamics simulation investigations. The docking studies of ligands against PARP1 and STAT3 were performed using the Glide module, in silico ADMET screening was performed using the quickprob module, binding energy calculation was performed using the Prime MM-GBSA module, MD simulation was performed using the Desmond module, and atomic charges were calculated using the Jaguar module of Schrodinger suite 2019-4. Of the substances studied, the derivative 1f has a considerable gliding score. The in silico ADMET characteristics are within the approved range. PRIME MM-GB/SA was used to compute the binding free energy, and the results are substantial. To investigate the dynamic behavior of the protein-ligand complex, compound 1f was subjected to MD simulation at 100 ns. The tested chemical 1f produced the greatest results in MD simulations and MM-GBSA calculations, indicating that this ligand can inhibit more effectively. Communicated by Ramaswamy H. Sarma

Computational prediction of 11β-hydroxysteroid dehydrogenase inhibitors from n-butanol fraction of Blighia welwetschii (Hiern) leaf for the management of type-2 diabetes

Human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) is an enzyme that catalyzes the generation of active cortisol from cortisone, thus regulating the availability of glucocorticoids for the steroid receptor. The involvement of this process in insulin insensitivity has established the catalyst as therapeutic target in type-2 diabetes management. Herein, potent antagonists of 11β-HSD-1 were predicted from bioactive compounds identified from n-butanol fraction of B. welwitschi leaf using chromatography method (HPLC). Molecular docking, MM/GBSA evaluation, autoQSAR modeling, e-pharmacophore modeling, and molecular dynamics simulation of the bioactive compounds were carried out against 11β-HSD-1 employing Schrodinger suite (2017-1). Seven out of the ten bioactive compounds from the fraction showed a higher degree of binding affinity against 11β-HSD-1 compared with the co-crystalized ligand. The post-docking analysis revealed strong interaction due to the hydrogen bond formation between the molecules and amino acid present at the catalytic site of 11β-HSD-1. Rutin showed the highest binding affinity (-13.980 kcal/mol) among the hits comparable to the co-crystalized ligand (-7.576 kcal/mol). The binding free energy (ΔGbind) evaluation validates the inhibitory potential of the docked complexes, which exclusively confirmed cyaniding-3-o-glucoside (-62.022 kcal/mol) with the highest binding energy followed by rutin (-59.629 kcal/mol). The molecular dynamics simulations predicted the stability of rutin and quercetin-3-o-glycoside complex with 11β-HSD-1 through 100 ns with minimum fluctuation and more H-bond observed between the two top scored 11β-HSD-1-compound complexes compared to the 11β-HSD-1-co-crystalized ligand complex. The pharmacokinetic profile revealed that the hit compounds are promising drug candidates except for rutin which violated more than one Lipinski’s rule of five. This study revealed that bioactive compounds identified from B. welwitschi leaves demonstrated good inhibitory potential against 11β-HSD-1. Therefore, these bioactive molecules require experimental validation as 11β-HSD-1 antagonists for type 2 diabetes management. Communicated by Ramaswamy H. Sarma

DOCKING STUDIES OF INDOLE ASSIMILATED PYRAZOLINE MOLECULAR HYBRIDS: DESIGN, SYNTHESIS AS ANTIINFLAMMATORY AGENTS AND ANTICANCER AGENTS

A series of novel compounds (4a-4l) have been synthesized by Claisen-Schmidt condensation, Schiff’s base and Cyclization mechanism. All the molecule structures were affirmation by IR, 1H NMR and Mass spectral data. The synthesized hybrids were screened for in vivo anti-inflammatory and invitro anticancer activities. Ant inflammatory activity was performed using carrageenan induced rat paw edema method using Diclofenac as standard drug. The anticancer activity has been assessing by using MTT assay against MCF7 and SKOV3 cell lines and Doxorubicin was used as reference standard. Among the compounds compound 4l exhibited the highest % inhibition of 98.4 when compared with the standard Diclofenac 94.2%.Compound 4f exhibited the lowest IC50 at concentration of 20.01µg against MCF7 cell lines and 32.87µg against SKOV3 cell lines. The molecular docking studies was performed using the Ligprep tool of Schrodinger suite. This study revealed that novel thiazolidne-4-one-pyrazole hybrids(4a-4j) had good interaction with the active site of EGFR receptor. Among the docked compounds, dock score of the compounds ranged from from -3.186 to -5.212. The highest score was exhibited by 4f with -5.212 with Glide binding energy of -34.697 Kcal/mol.

Insilico molecular modelling to identify PDK-1 targeting agents based on its protein–protein docking interaction

PDK1, an attractive cancer target that downstreams 23 other kinases towards cell growth, survival and metabolism has gaining attention due to allosteric effect of ligands bound to it. Generally, the drug design strategy using pharmacophores is either a single protein structure or ensemble or ligand-based. Apart from these methods, yet another new approach of protein–protein docking with state of art computational tool like Schrodinger Suite to generate pharmacophores based on the interacting partners of the protein is proposed in this work. The structure-based pharmacophoric features were picked up from docking the ten interacting partners of PDK1 and screened against the Enamine libraries containing protein–protein interacting compound collection, advanced, protein mimetic and allosteric compounds. High throughput virtual screening against the PIF pocket of PDK1 yields an indole scaffold. The identified indole derivative is proposed to be a strong activator that binds in the protein–protein interaction site of PDK1 which was further confirmed by molecular metadynamics simulations, free energy surface analysis and MM-GBSA calculations. Thus, the pharmacophores generated by the interacting proteins for PPI can facilitate the virtual screening in structure-based drug discovery of similar therapeutic targets. Communicated by Ramaswamy H. Sarma

Phytoligands analysis of aqueous seed extract of Momordica charantia Linn. via GC-MS for its antidiabetic activity

In India, Momordica charantia Linn. is utilized in juices, health supplements and colouring agents. The aim of the current study is to analyze phytoligands by utilizing gas chromatography mass spectroscopy of aqueous seed extract of Momordica charantia Linn (MCA). The MCA was prepared by macerating the powdered seeds for 72 hrs followed by filtration and lyophilization followed by an in vitro α-glucosidase inhibitory activity. MCA was the potent inhibitor of α-glucosidase with IC50 value 73.75± 0.05 μg/ml. The analysis through GC-MS investigated 60 phytoconstituents which were validated using Schrodinger suite version 2020-3 against α-glucosidase (PDB ID- 5NN5). As per docking results, the existing phytochemicals azetidin-2-one 3,3-dimethyl-4-(1-aminoethyl)-, alpha-l-rhamnopyranose, piperidine, 3-methyl-, 1,4-Dioxane-2,5-dione,3,6-dimethyl and citronellol epoxide (R or S) from MCA, got the highest d-score of -7.230, -5.918, -5.643, -5.312 and -5.185 kcal/mol and could be promising antidiabetic drug candidates.

Hecogenin a Plant Derived Small Molecule as an Antagonist to BACE-1: A Potential Target for Neurodegenerative Disorders.

The field of drug discovery has recognized the significance of computer-aided drug design. Recent advancements in structure identification and characterization, bio-computational science and molecular biology have significantly contributed to the development of novel treatments for various diseases. Alzheimer's disease is prevalent in over 50 million affected people, with the pathological condition of amyloidal plaque formation by the beta-amyloidal peptide that results in lesions of the patient's brain, thus making the target prediction and treatment a hurdle. In this study, we evaluated the potential of 54 bioactive compounds from Justicia adhatoda L. and Sida cordifolia L. identified through LC-MS/MS against the β-site amyloid precursor cleaving enzyme (beta-secretase) that results in the formation of amyloidal plaques. To study the drug-likeness of the phytocompounds, Lipinski's rule of five for ADME profiling and toxicity prediction was performed. Molecular docking was performed using auto-dock tool of PyRx software; molecular dynamic simulations were performed using the Schrodinger suite. Molecular docking against BACE-1 protein revealed that hecogenin, identified from S. cordifolia has a broad spectrum of pharmacological applications and a binding affinity score of -11.3 kcal/Mol. The Hecogenin-BACE-1 protein complex was found to be stable after 30 ns of MD simulation, resulting in its substantial stability. Further studies focusing on the in vivo neuroprotective activity of hecogenin against the disease will pave the way for efficient drug discovery from natural sources in a precise manner.

Identification of novel scaffolds to inhibit Mycobacterium tuberculosis PimA protein-A computational approach.

Phosphatidyl-myo-inositol mannosyltransferase (Pim) is a subset of the Glycosyl transferase type family that has been synthesized from 1D-myo-inositol and GDP-α-d-mannose reaction in the presence of PimA protein as a catalyst, which PimA protein is identified as a high-confidence therapeutic target. In-silico technique such as homology modeling is the most efficient approach for discovering a new framework to study the modulations of protein function. Using In-silico approaches, therapeutic compounds with high affinity, specificity, activity, low harmfulness, and no side effects can be found. Applying the Modeller software and molecular dynamics simulations, a stable three-dimensional (3D) model of the PimA protein is produced. The modeled PimA protein consists of 20 helices and 27 twists in its 3D structure. Lead compounds that inhibit the PimA protein are found by applying the Schrodinger suite and the PyRx virtual screening tools. The amino acid residues PRO14 and ASP253 are identified as active residues involved in binding with the ligands. High-potential lead compounds are discovered as ligand scaffolds against PimA protein with satisfactory ADME capabilities.

Novel pseudonucleosides and sulfamoyl-oxazolidinone β-D-glucosamine derivative as anti-COVID-19: design, synthesis, and in silico study

New pseudonucleosides containing cyclic sulfamide moiety and sulfamoyl β-D-glucosamine derivative are described. These pseudonucleosides are synthesized in good yields starting from chlorosulfonyl isocyanate and β-D-glucosamine hydrochloride in five steps; (protection, acetylation, removal of the Boc group, sulfamoylation, and cyclization). Further, novel glycosylated sulfamoyloxazolidin-2-one is prepared in three steps; carbamoylation, sulfamoylation, and intramolecular cyclization. The structures of the synthesized compounds were confirmed by usual spectroscopic and spectrometric methods NMR, IR, MS, and EA. Interesting molecular docking of the prepared pseudonucleosides and (Beclabuvir, Remdesivir) drugs with SARS-CoV-2/Mpro (PDB:5R80) was conducted using the same parameters for a fair comparison. A low binding affinity of the synthesized compounds compared to the Beclabuvir and other analysis showed that pseudonucleosides have the ability to inhibit SARS-CoV-2. After the motivating results of molecular docking study, the complex between the SARS-CoV-2 Mpro and compound 7 was subjected to 100 ns molecular dynamics (MD) simulation using Desmond module of Schrodinger suite, during which the receptor-ligand complex showed substantial stability after 10 ns of MD simulation. Also, we studied the prediction of absorption, distribution, properties of metabolism, excretion, and toxicity (ADMET) of the synthesized compounds. Communicated by Ramaswamy H. Sarma

In silico evaluation of some commercially available terpenoids as spike glycoprotein of SARS-CoV-2 – inhibitors using molecular dynamic approach

Coronavirus, an extremely contagious infections disease had a harmful effect on the world’s population. It is a family of enveloped, single-stranded, positive-strand RNA viruses of Nidovirales order belongs to coroviridae family. At present, worldwide several lakhs of deaths and several billions of infections have been reported. Hence, the focus of the present study was to assess the SARS-CoV-2 enzyme inhibitory potential of certain commercially available terpenoids using Lamarckian genetic algorithm as a working principle and molecular dynamic studies was also performed. AutoDock 4.2 software was used to perform the computational docking calculations of terpenoids against SARS-CoV-2 enzyme. The terpenoids such as, Andrographolide, Betulonic acid, Erythrodiol, Friedelin, Mimuscopic acid, Moronic acid, and Retinol were selected based on the drug likeness properties. Remdesivir a well-known anti-viral drug was selected as the standard drug. Molecular dynamic simulation studies were carried using Desmond module of Schrodinger Suite. In the current study we observed that, Friedelin was exhibited excellent SARS-CoV-2 enzyme inhibitory potential than the standard drug and other selected terpenoids. Friedelin and the standard Remdesivir was undergone the molecular dynamic studies and Friedelin showed a good number of hydrogen bonds over the simulation time of 100 ns. Based on the in silico computational evaluation, it can be concluded that Friedelin could be worthwhile terpenoid against SARS-CoV-2 spike protein. A further study on Friedelin is required to develop a potential chemical entity against the management of COVID disease. Communicated by Ramaswamy H. Sarma

Cancer Therapeutics: Structure-Based Drug Design of Inhibitors for a Novel Angiogenic Growth Factor

Angiogenesis, the formation of new blood vessels, is a critical and rate-limiting tumor growth step controlled by pro-angiogenic factors and specific inhibitors. Tumor angiogenesis is essential for cancer progression and metastasis. Platelet growth factors (PDGF) and their receptors (PDGFR) are associated with tumor angiogenesis through overexpression of PDGF. Inhibition of PDGF and its signaling pathway is a new approach to the discovery of anticancer therapeutic agents. The present study focuses on the PDGF-C protein in the identification of novel anti-angiogenic compounds. MODELLER 9.10 software allows users to create and refine a 3D homology model of the PDGF-C protein (345 a.a. length). Secondary structure analysis of the 3D energy model reveals 16 β sheets held together by four cation–π and one π–σ interactions, and three salt bridges. The quality of the model is assessed using the Ramachandran plot (90 percent amino acids in the favorable region) and the ProSA server (Z-score = –2.28). Active site residues are identified using Castp, QSite search engine, site map, and protein docking of the protein to its receptor. In addition, virtual screening is performed at the active site using the Glide module of the Schrodinger Suite. Glide score, glide energy and ADME are being measured to discover new benefits of pyrazolone and pyrrolidine-2,3-dione scaffolds as potent PDGF-C antagonists for anti-angiogenic cancer chemotherapy drugs.

Lactate Dehydrogenase Superfamily in Rice and Arabidopsis: Understanding the Molecular Evolution and Structural Diversity.

Lactate/malate dehydrogenases (Ldh/Maldh) are ubiquitous enzymes involved in the central metabolic pathway of plants and animals. The role of malate dehydrogenases in the plant system is very well documented. However, the role of its homolog L-lactate dehydrogenases still remains elusive. Though its occurrence is experimentally proven in a few plant species, not much is known about its role in rice. Therefore, a comprehensive genome-wide in silico investigation was carried out to identify all Ldh genes in model plants, rice and Arabidopsis, which revealed Ldh to be a multigene family encoding multiple proteins. Publicly available data suggest its role in a wide range of abiotic stresses such as anoxia, salinity, heat, submergence, cold and heavy metal stress, as also confirmed by our qRT-PCR analysis, especially in salinity and heavy metal mediated stresses. A detailed protein modelling and docking analysis using Schrodinger Suite reveals the presence of three putatively functional L-lactate dehydrogenases in rice, namely OsLdh3, OsLdh7 and OsLdh9. The analysis also highlights the important role of Ser-219, Gly-220 and His-251 in the active site geometry of OsLdh3, OsLdh7 and OsLdh9, respectively. In fact, these three genes have also been found to be highly upregulated under salinity, hypoxia and heavy metal mediated stresses in rice.

3D-QSAR, design, docking and in silico ADME studies of indole-glyoxylamides and indolyl oxoacetamides as potential pancreatic lipase inhibitors

The versatility of indole heterocyclic led to the understanding of their structural requirements to develop new potential derivatives. The indole derivatives estimated to be active against pancreatic lipase have been chosen to develop 3D-QSAR field and atom-based models, validated using the Schrodinger suite. Designing of new agents through QSAR based predictions and performing docking on these compounds helped in defining the binding pattern and pharmacophoric features like π–π stacking interactions, hydrogen bonding, and π-cation interactions with the amino acid residues. The protein-ligand complex displayed good binding energies. In silico ADMET properties have been generated using the Quick-prop module of the Schrodinger suite. The 3D-QSAR model is found to be statistically significant and evaluated using various parameters like R2, R2CV, stability, F-value, P-value, RMSE, Q2, and Pearson-r by PLS factor of 4. The field fractions and contour maps along with their visualizations have helped in inferring the essential nature and type of substituent that should be incorporated for a compound to display potent pancreatic lipase inhibitory activity. These deductions and evaluations of the synthesized compounds through the generation of models could be further utilized for designing new molecules rationally.

An In-silico Approach: Design, Homology Modeling, Molecular Docking, MM/GBSA Simulations, and ADMET Screening of Novel 1,3,4-oxadiazoles as PLK1inhibitors.

Breast cancer is the most commonly diagnosed and major cause of cancer-related deaths in women worldwide. Disruption of the normal regulation of cell cycle progression and proliferation are the major events leading to cancer. Human Polo-like Kinase 1 (PLK1) plays an important role in the regulation of cellular division. High PLK1 expression is observed in various types of cancer including breast cancer. 1,3,4-oxadiazoles are the fivemembered heterocycles, that serve as versatile lead molecules for designing novel anticancer agents and they mainly act by inhibiting various enzymes and kinases. A novel series of 1,3,4-oxadiazole derivatives (A1-A26) were designed and subjected to an in-silico analysis against PLK1 enzyme (PDB ID:1q4k), targeting breast cancer. The chemical structure of each compound (A1-26) was drawn using ChemDraw software. The 3D structure model of protein target (PDB ID:1q4k) was built using the SWISSMODEL server. Molecular docking simulation was performed to determine the designed compound's probable binding mode and affinity towards the protein target (PDB ID:1q4k). The designed compounds were subjected to ADME screening, as well as Prime MM/GBSA simulations using Schrodinger suite 2020-4. Furthermore, the safety profile of compounds was examined through the OSIRIS property explorer program and the results were compared with the standard drugs, 5-fluorouracil and cyclophosphamide. Based on the binding affinity scores, the compounds were found selective to target protein 1q4k through hydrogen bonding and hydrophobic interactions. The compounds A11, A12, and A13 were found to have higher G scores and binding free energy values. The ADME screening results were also found to be within the acceptable range. Moreover, the in-silico toxicity prediction assessments suggest that all designed compounds have a low risk of toxicity, and have higher efficiency for the target receptor. The study showed that the substitution of electron-donating groups at the various position of the aromatic ring, which is bonded at the second position of the substituted 1,3,4- oxadiazole nucleus resulted in compounds with good binding energy and G score compared to the standard drugs, and hence, they can be further developed as potent PLK1 enzyme inhibitors.