Prime MM-GBSA Research Articles

Identification of coastal pesticide pollutants as potent inhibitors of Bacillus pasteurii urease mediated calcium carbonate precipitation: a computational approach

Microbially induced calcite precipitation (MICP) through urease enzyme has attained a lot of recognition in various fields of civil engineering and geotechnology for stabilizing the strength of soil and various concrete materials. The activity of urease has been found to be affected by various factors like temperature, substrate concentrations, pH of the medium, presence of inhibitors, etc. Through this study, the outcome of the interaction of pesticides (commonly found in Indian coastal regions) on Bacillus pasteurii urease, a major organism reported for MICP studies has been investigated in silico. The results from the study revealed that the enzyme has higher interactions of −4.1, −3.2, and −3.4 kJ/mol with common pesticides like dichloro diphenyl dichloro ethane(DDD), dichloro diphenyl trichloroe thane (DDT), and methyl parathion of organochlorides and organophosphates class. From the molecular dynamics simulation analysis, complex 1 (DDD -receptor) has been found to have the highest and more compact structure followed by methyl parathion -receptor. Prime MM-GBSA analysis also revealed the highest binding energy of −27.8 kcal/mol with the protein and DDD. Thus, it can be inferred from the current study that pesticides, particularly, DDD, DDT, and methyl parathion present in the coastal areas may have an impact on urease. This interaction can result in the inhibition of the urease activity of B. pasteurii, thus preventing the biomineralization process. This study would be the first report on the computational approach to understanding the interaction of prominent pesticides on the coastal region and B. pasteurii urease. Communicated by Ramaswamy H. Sarma

Understanding the electronic structure of the alkaloid in scorpion venom through drug adsorption and molecular docking studies on COVID-19 proteins

Electronic structure analysis of the alkaloid from scorpion venom (ASV) was studied at the B3LYP/6-311++G (d, p) level of theory. Vibrational analysis, molecular orbital analysis and the MEP and contour plot analysis show the reactivity and molecular stability of the compound. The measured frontier molecular orbital energy distance (ELUMO-EHOMO) is 4.12 eV. The reactive descriptors research found that the ASV molecule has a chemical hardness of 2.205 eV and an electronegativity of 3.325 eV, consistent with its biological activity. The calculated NLA parameters μo, αo, and β° values of the title molecule are 1.5009 Debye, −5.718 × 10-24 e.s.u, 2.984 × 10-30 e.s.u, respectively. The alkaloid from scorpion venom is found to form stable complexes with cyclodextrin. ASV was docked against the main proteases (MPro) and papain-like proteases (PLpro) of COVID-19. ASV has a Glide docking score of -8.017 kcal/mol with MPro and -5.091 kcal/mol with PLpro. ASV has a Prime MM-GBSA binding score of -51.74 kcal/mol with MPro and -32.19 kcal/mol with PLpro. The Glide and Prime results demonstrated that ASV has a stronger binding for MPro than PLpro protein. Furthermore, the major pharmacokinetic characteristics of ASV were predicted. ASV was found to have good drug-like properties with no violations. Since ASV binds to COVID-19 proteases, it could be used as an anti-COVID-19 agent. The outcomes of the study may have a substantial impact on the development of COVID-19 therapies.

New Thiazole Carboxamide Derivatives as COX Inhibitors: Design, Synthesis, Anticancer Screening, In Silico Molecular Docking, and ADME Profile Studies.

The goal of this work was to create and test a new series of thiazole carboxamide derivatives for their cyclooxygenase (COX) suppressor and anticancer effects. The compounds were characterized using 1H, 13C NMR, and HRMS spectrum analysis, and their selectivity toward COX-1 and COX-2 was assessed using an in vitro COX inhibition assay kit. Cytotoxicity was assessed using an MTS assay against a panel of cancer and normal cell lines. The docking studies were aided by the Prime MM-GBSA method for estimating binding affinities. The density functional theory (DFT) analysis was performed to assess compound chemical reactivity, which was calculated by computing the border orbital energy of both HOMO and LUMO orbitals, as well as the HOMO-LUMO energy gap. For ADME-T analysis, the QiKProp module was employed. Furthermore, using human X-ray crystal structures, molecular docking studies were carried out to discover the probable binding patterns of these drugs within both COX-1 and COX-2 isozymes. The results demonstrated that the most effective compound against the COX-1 enzyme was 2b with an IC50 of 0.239 μM. It also showed potent activity against COX-2 with an IC50 value of 0.191 μM and a selectivity ratio of 1.251. The highest selectivity ratio was 2.766 for compound 2a against COX-2 with an IC50 dose of 0.958 μM relating to the celecoxib ratio of 23.8 and its IC50 against COX-2 of 0.002 μM. Compound 2j also showed good selectivity toward COX-2 (1.507) with an IC50 value of 0.957 μM. All compounds showed negligible cytotoxic activity against the evaluated normal cell lines, and the IC50 values were more than 300 μM, except for compound 2b, whose IC50 values were 203.71 ± 1.89 and 116.96 ± 2.05 μM against LX-2 and Hek293t cell lines, respectively. Moreover, compound 2b showed moderate anticancer activity against COLO205 and B16F1 cancer cell lines with IC50 values of 30.79 and 74.15 μM, respectively.

Discovery of novel and highly potential inhibitors of glycogen synthase kinase 3-beta (GSK-3β) through structure-based pharmacophore modeling, virtual computational screening, docking and in silico ADMET analysis

The protein Glycogen Synthase Kinase 3-Beta (GSK-3β), is a promising therapeutic target for treating various diseases such as neurodegenerative disorders, diabetes, inflammation and cancer. This study aims to investigate the potential of compounds targeting inflammation or carbohydrate metabolism to selectively inhibit GSK3β by binding to its ATP site. To achieve this goal, we filtered a database of 49367 molecules involved in carbohydrate metabolism or targeting inflammation using various computational analyses, including pharmacophore modeling, molecular docking, dynamic simulation, prime MM-GBSA calculation, and in silico ADME studies. We generated a pharmacophore model (hypo S: AADDHRR) using two different crystallographic complexes of GSK3β and evaluated the model’s performance in identifying hits using various parameters, including EF, GH, ROC, AUC and BEDROC. Subsequently, we performed various dockings (HTVS, SP, XP and IFD) for the retrieved hits and found that, 5 out of the top 10 ranked compounds had the scaffold of pyrazolidine 3,5-dione, which has never been reported to inhibit kinases. We also conducted ADMET studies to and concluded that compound N6 exhibited the best pharmacokinetic profile passing the blood-brain barrier, possessing high lipophilicity and a high coefficient of skin permeability in the intestines, along with good bioavailability and low toxicity risk assessment. Dynamic simulation were also performed indicating that compounds N6 derived from pyrazolidine 3,5-dione demonstrated better binding potential for GSK3β during the simulation period. Therefore, we propose that compounds derived from pyrazolidine-3,5-dione, which modulate the activity of lysosomal alpha-glucosidase could serve as a novel scaffold for the selective inhibition of GSK-3β. Communicated by Ramaswamy H. Sarma

Novel topical anandamide formulation for alleviating peripheral neuropathic pain

Peripheral neuropathy (PN) is a condition of peripheral nerve damage leading to severe pain. The first line therapies are associated with adverse psychotropic effects (PSE) and second line therapies are not efficient enough to relieve pain. There is an unmet drug need for relieving pain effectively without PSE in PN. Anandamide, an endocannabinoid activates cannabinoid receptors to relieve the pain due to peripheral neuropathy (PN). Anandamide has a very short biological half-life as they are extensively metabolized by fatty acid amide hydrolase enzyme (FAAH). Regional delivery of safe FAAH inhibitor (FI) with anandamide would be beneficial for PN without PSE. The objective of the study is to identify a safe FI and deliver the anandamide in combination with the FI topically for the management of PN. The FAAH inhibition potential of silymarin constituents was evaluated by molecular docking and in vitro studies. The topical gel formulation was developed to deliver anandamide and FI. The formulation was assessed in chemotherapeutic agent-induced PN rat models to relieve mechanical-allodynia and thermal-hyperalgesia. The molecular docking studies demonstrated that the Prime MM-GBSA free energy of silymarin constituents were in the order of silybin > isosilybin > silychristin > taxifolin > silydianin. In in vitro studies, silybin 20 µM inhibited > 61.8% of FAAH activity and increased the half-life of anandamide. The developed formulation increased permeation of anandamide and silybin across the porcine skin. Furthermore, on the application of anandamide and anandamide–silybin gel to rat paws, there was a significant increase in the pain threshold for allodynic and hyperalgesic stimulus up to 1 h and 4 h, respectively. The topical anandamide with silybin delivery approach could serve to alleviate PN efficiently and thus could minimize unwanted CNS side effects of synthetic or natural cannabinoids in patients.

Discovery of potent DNMT1 inhibitors against sickle cell disease using structural-based virtual screening, MM-GBSA and molecular dynamics simulation-based approaches

Sickle cell disease (SCD) is an autosomal recessive genetic disorder affecting millions of people worldwide. A reversible and selective DNMT1 inhibitor, GSK3482364, has been known to decrease the overall methylation activity of DNMT1, resulting in the increase of HbF levels and percentage of HbF-expressing erythrocytes in an in vitro and in vivo model. In this study, a structure-based virtual screening was done with GSK3685032, a co-crystalized ligand of DNMT1 (PDB ID: 6X9K) with an IC50 value of 0.036 μM and identified 3988 compounds from three databases (ChEMBL, PubChem and Drug Bank). Using this screening method, we identified around 15 compounds with XP docking scores greater than −8 kcal/mol. Further, prime MM-GBSA calculations have been performed and found compound SCHEMBL19716714 with the highest binding free energy of −83.31 kcal/mol. Finally, four compounds were identified based on glide energy and ΔG bind scores that have the most binding with DG7, DG19, DG20 bases and Lys1535, His1507, Trp1510, Ser1230, which were required for the target enzyme inhibition. Furthermore, molecular dynamics simulation studies of top ligands validate the stability of the docked complexes by examining root mean square deviations, root mean square fluctuations, solvent accessible surface area, and radius of gyration graphs from simulation trajectories. These findings suggest that the top four hit compounds may be capable of inhibiting DNMT1 and that additional in vitro and in vivo studies will be essential to prove the clinical effectiveness of the selected lead compounds. Communicated by Ramaswamy H. Sarma

Virtual screening, molecular simulations and bioassays: Discovering novel microsomal prostaglandin E Synthase-1 (mPGES-1) inhibitors

Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible prostaglandin E synthase expressed following exposure to pro-inflammatory stimuli. The mPGES-1 enzyme represents a new target for the therapeutic treatment of acute and chronic inflammatory disorders and cancer. In the present study, compounds from the ZINC15 database with an indole scaffold were docked at the mPGES-1 binding site using Glide (high-throughput virtual screening [HTVS], standard precision [SP] and extra precision [XP]), and the stabilities of the complexes were determined by molecular simulation studies. Following HTVS, the top 10% compounds were retained and further screened by SP. Again, the top 10% of these compounds were retained. Finally, the Glide XP scores of the compounds were determined, 20% were analyzed, and the Prime MM-GBSA total free binding energies of the compounds were calculated. The molecular simulations (100 ns) of the reference ligand, LVJ, and the two best-scoring compounds were performed with the Desmond program to analyze the dynamics of the target protein-ligand complexes. In human lung cells treated with the hit compounds, cell viability by colorimetric method and PGE2 levels by immunoassay method were determined. These in vitro experiments demonstrated that the two indole-containing hit compounds are potential novel inhibitors of mPGES-1 and are, therefore, potential therapeutic agents for cancer/inflammation therapies. Moreover, the compounds are promising lead mPGES-1 inhibitors for novel molecule design.

Discovery, synthesis and in silico approach of pyrrolo [3,4-c]pyrroles as SARS-CoV-2 mpro inhibitors

A new coronavirus has been identified as the contributing agent of the severe acute respiratory syndrome (SARS). The main viral protease (Mpro), which controls the activities of the coronavirus replication complex, which is an essential target for the treatment of coronavirus disease. With the primary objective of targeting this receptor, we designed a new series of pyrrolo [3,2-c] pyrroles, synthesized and characterized using various analytical techniques including FT-IR, UV-Vis and NMR spectroscopic studies. The biological descriptors of the synthesized compounds were investigated using DFT calculation. The mode of binding and reactivity of the target compounds with SARS-CoV-2 main protease (Mpro) were studied using molecular docking and molecular dynamics (MD) simulation. Molecular docking of the compounds (4a and 5a) showed a promising binding affinity towards Mpro protein with the binding energy of −7.8 kcal/mol and −7.0 kcal/mol, respectively. The results of MD simulation and prime MM-GBSA calculation were consistent with molecular docking. The absorption, distribution, metabolism and excretion (ADME) properties of the compounds are in the acceptable range, as they are orally active and obey Lipinski’s rule of five without violation. In addition, in silico toxicity prediction using the Pro-Tox II revealed the non-toxic nature of the compounds. Hence the obtained results suggest that these compounds could be a possible anti-viral candidate and highlight this series of compounds for further drug design and development against SARS-CoV-2. Communicated by Ramaswamy H. Sarma

Multi-Targeting Approach in Selection of Potential Molecule for COVID-19 Treatment.

The coronavirus disease (COVID-19) is a pandemic that started in the City of Wuhan, Hubei Province, China, caused by the spread of coronavirus (SARS-CoV-2). Drug discovery teams around the globe are in a race to develop a medicine for its management. It takes time for a novel molecule to enter the market, and the ideal way is to exploit the already approved drugs and repurpose them therapeutically. We have attempted to screen selected molecules with an affinity towards multiple protein targets in COVID-19 using the Schrödinger suit for in silico predictions. The proteins selected were angiotensin-converting enzyme-2 (ACE2), main protease (MPro), and spike protein. The molecular docking, prime MM-GBSA, induced-fit docking (IFD), and molecular dynamics (MD) simulations were used to identify the most suitable molecule that forms a stable interaction with the selected viral proteins. The ligand-binding stability for the proteins PDB-IDs 1ZV8 (spike protein), 5R82 (Mpro), and 6M1D (ACE2), was in the order of nintedanib > quercetin, nintedanib > darunavir, nintedanib > baricitinib, respectively. The MM-GBSA, IFD, and MD simulation studies imply that the drug nintedanib has the highest binding stability among the shortlisted. Nintedanib, primarily used for idiopathic pulmonary fibrosis, can be considered for repurposing for us against COVID-19.

Bambusa vulgaris leaves reverse mitochondria dysfunction in diabetic rats through modulation of mitochondria biogenic genes.

There is evidence that mitochondrial dysfunction mediated by hyperglycemia increases the incidence of diabetes and age-related insulin resistance. Thus, maintaining mitochondrial integrity may provide alternative therapeutic approach in diabetes treatment. This study aimed to evaluate the effect of Bambusa vulgaris leaf extract on mitochondrial biogenesis in the pancreas of diabetic rats. 11weeks old male rats (n=30) were purchased, and sorted into the following groups: control, diabetic control, diabetes+metformin (100mg/kg), diabetes+Aq. B.vulgaris (100mg/kg), diabetes+Aq. B.vulgaris (200mg/kg), and diabetes+Aq. B.vulgaris (300mg/kg). Diabetes was induced in the rats by a single dose of 65mg/kg streptozotocin (STZ). The mRNA expression of genes related to mitochondria biogenesis (pgc-1α, Nrf2, GSK3β, AMPK and SIRT2) and genes of Nrf2-Keap1-ARE signaling pathway were determined by reverse transcriptase polymerase chain reaction. Molecular docking studies including lock and key docking and prime MM-GBSA were incorporated to identify the lead chemical compounds in Bambusa vulgari. The results showed that B.vulgaris leaf extract promotes mitochondrial biogenesis via altering the mRNA expression of mitochondrial master regulator pgc-1α, otherupstream genes, and the Nrf2-Keap1-ARE antioxidant pathway. Through molecular docking results, cryptochlorogenic acid, hesperidin, orientin, vitexin, scopolin, and neochlorogenic were found as the crucial chemicals in B.vulgaris with the most modulating effect on PGC-1α, AMPK, and GSK3. This study thus suggests that B.vulgaris leaf extract restores the integrity of mitochondria in diabetic rats.

Discovery of Pongol, the Furanoflavonoid, as an Inhibitor of CDK7/Cyclin H/MAT1 and Its Preliminary Structure-Activity Relationship.

Natural products have been a great source of leads for cancer drug discovery. The cyclin-dependent kinases (CDKs) play a vital role in the initiation and progression of cancer. The CDK-activating kinase, CDK7/cyclin H/MAT1, has recently gained tremendous attention in targeted cancer drug discovery. Herein, we screened a small library of pure natural products in an ADP-Glo CDK7/H kinase assay that yielded a series of furano- and naphthoflavonoids among actives. Pongol (SBN-88), the hydroxy-substituted furanoflavonoid, inhibits CDK7/H as well as CDK9/T1 with IC50 values of 0.93 and 0.83 μM, respectively, and >20-fold selectivity over CDK2/E1 (IC50 > 20 μM). The molecular docking and molecular dynamics simulation revealed that the presence of phenolic -OH in pongol is vital for kinase inhibition, as its absence resulted in a significant loss in activity (e.g., lanceolatin B). The prime MM-GBSA calculations revealed the presence of strong lipophilic and H-bonding interactions of pongol with CDKs.

Assessment of a Computational Approach to Predict Drug Resistance Mutations for HIV, HBV and SARS-CoV-2.

Viral resistance is a worldwide problem mitigating the effectiveness of antiviral drugs. Mutations in the drug-targeting proteins are the primary mechanism for the emergence of drug resistance. It is essential to identify the drug resistance mutations to elucidate the mechanism of resistance and to suggest promising treatment strategies to counter the drug resistance. However, experimental identification of drug resistance mutations is challenging, laborious and time-consuming. Hence, effective and time-saving computational structure-based approaches for predicting drug resistance mutations are essential and are of high interest in drug discovery research. However, these approaches are dependent on accurate estimation of binding free energies which indirectly correlate to the computational cost. Towards this goal, we developed a computational workflow to predict drug resistance mutations for any viral proteins where the structure is known. This approach can qualitatively predict the change in binding free energies due to mutations through residue scanning and Prime MM-GBSA calculations. To test the approach, we predicted resistance mutations in HIV-RT selected by (-)-FTC and demonstrated accurate identification of the clinical mutations. Furthermore, we predicted resistance mutations in HBV core protein for GLP-26 and in SARS-CoV-2 3CLpro for nirmatrelvir. Mutagenesis experiments were performed on two predicted resistance and three predicted sensitivity mutations in HBV core protein for GLP-26, corroborating the accuracy of the predictions.

Identification of new anti-cancer agents against CENTERIN: Structure-based virtual screening, AutoDock and binding free energy studies

Lymphoma is a distinctive blood cell cancer affecting lymphocytes, immune cells which are crucial in killing cancer cells and maintaining immune responses. Targeting CENTERIN protein can be an excellent strategy for the identification of new anticancer drugs. Over expression of CENTERIN protein and covalent binding with serine protease leads to cell progression in many lymphomas, mainly Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Understanding the 3D structure of CENTERIN is essential to identify potential inhibitors against CENTERIN protein. The 3D structure of CENTERIN protein was built using homology modeling techniques and the resulting protein is energy minimized by the NAMD-VMD server. The protein is further validated and active site identification is carried out using SiteMap by Schrodinger suite and literature studies. A structure-based virtual screening study with the TosLab database and current cancer therapeutics was carried out in Schrodinger suite and AutoDock softwares to identify better ligand molecules showing more binding affinity towards CENTERIN protein. The molecules with more acceptable docking scores and favorable ADME properties with effective binding energies visualized from AutoDock and Prime MMGBSA will be treated as dominant CENTERIN inhibitors for cancer treatment. Molecular dynamics simulation studies suggested the support of novel lead molecule M1 as potential inhibitor of CENTERIN protein.

A computational evaluation of FDA medicines' ability to inhibit hypoxia-inducible factor prolyl hydroxylase-2 (PHD-2) for acute respiratory distress syndrome.

COVID-19 infection is associated with a significant fatality rate in individuals suffering from severe acute respiratory distress syndrome (ARDS). Among the several possibilities, inhibition of hypoxia-inducible factor prolyl hydroxylase-2 or prolyl hydroxylase domain-containing protein 2 (PHD2) in a hypoxia-independent way is a prospective therapeutic target for the treatment of ARDS. Vadadustat, Roxadustat, Daprodustat, Desidustat, and Enarudustat are the available clinical trial inhibitors. This study is proposed to focus on the repurposing of FDA-approved drugs as effective PHD2 inhibitors. This computational study utilises e-pharmacophore hypothesis generation from the native ligand–protein complex (PDB ID: 5OX6) based on XP visualiser information. The hypothesis containing five essential features (AAANR) was incorporated for FDA database screening, followed by Glide XP molecular docking and Prime MM-GBSA binding free energy calculations. Top scored ligands were investigated and Fenbufen was identified as an effective PHD-2 inhibitor by comparing with the native co-crystal ligand (Vadadustat). The manual lead optimisation of the Fenbufen structure was adopted to improve inhibitory potency, by increasing the binding affinity and protein–ligand stability. The newly designed compounds B and C showed additional binding interactions, excellent docking scores, binding free energy, and an acceptable range of ADME properties. Also, Fenbufen and compound C owned preferable protein–ligand stability during MD simulation when compared with the co-crystallised clinical trial ligand. Based on our findings, we deduce that Fenbufen can be proposed as an effective repurposable candidate as its structural modification showed a remarkable improvement in PHD2 inhibition.Graphical abstract Supplementary informationThe online version contains supplementary material available at 10.1007/s11224-022-02012-z.

Anticancer, antioxidant, and antimicrobial properties of solvent extract of Lobophora variegata through in vitro and in silico studies with major phytoconstituents

Seaweeds possess a wide range of bioactive compounds which have been play a vital role in production of novel pharmaceutical and nutraceutical products resources. The present study employed in silico molecular docking to characterize the biomedical potential of brown seaweed Lobophora variegata through antibacterial, antibiofilm, antioxidant and anticancer activities. The antibacterial activity of L. variegata extracts was analyzed against Escherichia coli, Enterococcus faecalis, Staphylococcus aureus, and Pseudomonas aeruginosa strains producing biofilms. The antioxidant activity was assessed using (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)), superoxide, and hydroxyl radical scavenging assays. Further, the anticancer, antibacterial, and antioxidant activities of the bioactive compounds were evaluated through molecular docking using GLIDE ligand docking module and prime MM-GBSA module in the Schrodinger software. The phytochemical analysis of the methanolic extract of L. variegata found more phycocompounds which was confirmed by FT-IR and GC-MS. The significant level of phenol and flavonoid were expressed in methanolic extract of L. variegata. In addition, the potent antioxidant activity of the methanolic extract was efficiently expressed during the free radical scavenging assays of ABTS, hydroxyl, and superoxide denoted as 34.94, 26.64, and 29.86 mg/g, respectively. The antibacterial and biofilm activities of the methanolic extract of L. variegata had significant results. Moreover, the methanolic extract exhibited cytotoxicity against human colon cancer HT-29 cell lines at an inhibitory concentration is 193.65 μg/mL. Through the computational analysis, glyceryl monostearate, 2-palmitoylglycerol, phthalic acid, 2-chloropropyl ethyl ester, phthalic acid, 5-methylhex-2-yl ethyl ester, and l-(+)-ascorbic acid 2,6-dihexadecanoate results as top ranked molecules and shown to be a promising compounds, which were evaluated for anticancer, antioxidant, and antibacterial properties against multi-target proteins. Based on the experimental results, L. variegata could be a valuable marine source for developing novel pharmaceutical applications.

Molecular docking and dynamics approach to in silico drug repurposing for inflammatory bowels disease by targeting TNF alpha

Inflammatory bowel disease is a chronic disorder of the large intestine with the prevalence of approximately 400 cases in 100000, and it is rising day by day. However, several drugs like sulfasalazine (composed of sulfapyridine and 5-aminosalicylic acid or 5-ASA), corticosteroids, and immunosuppressants manage the disease. But there are no absolute treatments for the pain and inflammation of the disease. TNFα is an important target, and drugs like infliximab and adalimumab have pharmacological potency but with pronounced toxicity. So, we choose this major target TNFα for the virtual screening of US-FDA-approved drugs for its repurposing using the in silico method. The protein TNFα (PDB ID: 2AZ5) with small molecule inhibitor and the US-FDA-approved drug molecules (from Zinc database) were first imported and prepared using Protein Preparation Wizard and LigPrep, respectively, followed by molecular docking, ADMET analysis and prime MMGBSA. After that, the drugs were shortlisted according to dock score, ADMET parameters and MM GBSA dG binding score. After that, the shortlisted drug molecules were subjected to an induced-fit docking analysis. Two of the most promising molecules, ZINC000003830957 (Iopromide) and ZINC000003830635 (Deferoxamine), were chosen for molecular dynamics simulation. Finally, the bioisosteric replacement was used to improve the ADMET properties of these molecules. This research provides an idea for drug exploration and computational tools for drug discovery in treating inflammatory bowel disease. Communicated by Ramaswamy H. Sarma

Phytochemical Characterization, Functional Nutrition, and Anti-Diabetic Potentials of Leptadenia hastata (pers) Decne Leaves: In Silico and In Vitro Studies.

The geometrical increase in diabetes mellitus (DM) and the undesirable side effects of synthetic drugs have intensified efforts to search for an effective and safe anti-diabetic therapy. This study aimed to identify the antioxidant and anti-diabetic agents in the ethanol extract of Leptadenia hastata (EELH). The phytochemicals, antioxidant vitamins, and minerals present in EELH were determined using standard procedures to achieve this aim. Gas chromatography coupled with mass spectroscopy and flame ionization detector (GC-MS/GC-FID) was employed to identify bioactive compounds. An e-pharmacophore model was generated from the extra precision, and energy-minimized docked position of standard inhibitor, acarbose onto human pancreatic amylase (HPA, PDB-6OCN). It was used to screen the GC-MS/GC-FID library of compounds. The top-scoring compounds were subjected to glide XP-docking and prime MM-GBSA calculation with the Schrodinger suite-v12.4. The Adsorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) prediction of the best-fit compounds was made using SwissADME and PROTOX-II webservers. Further validation of the docking results was performed with the in vitro analysis of the α-amylase and α-glucosidase inhibitory activities. EELH contains appreciable amounts of antioxidant and anti-diabetic phytoconstituents. The top-4 scoring compounds (rutin, epicatechin, kaempferol, and naringenin) from the EELH phytochemical library interacted with amino acid residues within and around the HPA active site. The ADMET prediction shows that epicatechin, kaempferol, and naringenin had favorable drug-likeness, pharmacokinetic properties, and a good safety profile. EELH demonstrated good inhibitory actions against α-amylase and α-glucosidase with 1C50 values of 14.14 and 4.22 µg/mL, respectively. Thus, L hastata phytoconstituents are promising novel candidates for developing an anti-diabetic drug.

An insight into SARS-CoV-2 membrane protein interaction with spike, envelope, and nucleocapsid proteins

Intraviral protein–protein interactions are crucial for replication, pathogenicity, and viral assembly. Among these, virus assembly is a critical step as it regulates the arrangements of viral structural proteins and helps in the encapsulation of genomic material. SARS-CoV-2 structural proteins play an essential role in the self-rearrangement, RNA encapsulation, and mature virus particle formation. In SARS-CoV, the membrane protein interacts with the envelope and spike protein in Endoplasmic Reticulum Golgi Intermediate Complex (ERGIC) to form an assembly in the lipid bilayer, followed by membrane-ribonucleoprotein (nucleocapsid) interaction. In this study, we tried to understand the interaction of membrane protein’s interaction with envelope, spike, and nucleocapsid proteins using protein–protein docking. Further, simulation studies were performed up to 100 ns to examine the stability of protein–protein complexes of Membrane-Envelope, Membrane-Spike, and Membrane-Nucleocapsid proteins. Prime MM-GBSA showed high binding energy calculations for the simulated structures than the docked complex. The interactions identified in our study will be of great importance, as it provides valuable insight into the protein–protein complex, which could be the potential drug targets for future studies. Communicated by Ramaswamy H. Sarma

Identification of Papain-Like Protease inhibitors of SARS CoV-2 through HTVS, Molecular docking, MMGBSA and Molecular dynamics approach.

Coronaviruses (CoVs) are a large group of enveloped positive sense single-stranded RNA viruses that can cause disease to humans. These are zoonotic having potential to cause large-scale outbreaks of infections widely causing morbidity and mortality. Papain-Like Proteases (PLpro) is a cysteine protease, essential for viral replication and proliferation, as a highly conserved enzyme it cleaves peptide linkage between Nsp1, Nsp2, Nsp3, and Nsp4. As a valid therapeutic targets it stops viral reproduction and boosts host immune response thereby halting further spread of infection. In the purpose of identifying inhibitors targeting Papain-Like Proteases (PLpro) we initiated a high throughput virtual screening (HTVS) protocol using a SuperNatural Database. The XP docking results revealed that two compounds SN00334175 and SN00162745 exhibited docking score of -10.58 kcal/mol and -9.93 kcal/mol respectively. The Further PRIME MMGB-SA studies revealed Van der Waal energy and hydrophobic energy terms as major contributors for total binding free energy. The 100 ns molecular dynamics simulation of SN00334175/7JN2 and SN00162745/7JN2 revealed that these complexes were stabilized with ligand binding forming interactions with Gly266, Asn267, Tyr268, Tyr273, Thr301 and Asp302, Lys157, Leu162, Asp164, Arg166, Glu167, Pro248, Tyr264.

Computational investigations of structural and interactive patterns of human MTHFR wild and mutant type under different physiological conditions: An insight into underlying perturbations.

Methylene Tetrahydrofolate Reductase (MTHFR), involved in regulation of methionine and folate synthesis is a potential marker of Alzheimer's Disease (AD). Metabolic folate pathways along with methyl donor reactions are crucial in AD pathogenesis. A222V mutation denatures MTHFR due to thermolability and deranges methionine and folate levels resulting in increased plasma homocysteine levels. Also, there occurs increased GSK3β and decreased Protein Phosphatase 2A levels which are anticipated to be involved in phosphorylation of Amyloid β and Tau proteins. In this study, structural and interactive patterns of wild type and mutated (A222V) MTHFR with the substrate FAD were studied. X-ray crystallographic structure of MTHFR (PDB ID: 6CFX) was retrieved from PDB. The mutant protein was created by mutating A to V at 222nd position. The models were validated through ERRAT, Verify 3D and PROCHECK servers. Structure of FAD was retrieved and redocked at the same positions of created homodimer and Prime MM-GBSA was calculated for both wild and mutant protein complexes. The ligand behaviour at different pH and temperatures were studied using Desmond and GROMACS respectively. The stability and interactive patterns of the complexes were studied through Molecular Dynamics. Protein and ligand RMSD, RMSF, Radius of Gyration (RoG), Solvent accessible surface, secondary structure changes and MM-PBSA were examined. The created homodimers were found to be stable and around 89% of the residues were found to be present in favoured regions of Ramachandran plot. ERRAT and Verify 3D plots yielded best results. No much variations in docking scores of FAD ligands in both chains of the proteins were observed; whereas slight variations were seen in the MM-GBSA and MM-PBSA energies of the ligands. FAD in chain A was found to possess high energies rather than FAD in chain B in both proteins. RMSD, RMSF and RoG were found to be stable throughout the simulations. The behaviour of FAD was found to be different in mutated type at different temperatures. Computational studies offer better insights into the structural changes in proteins and their relationship with disease conditions.