Stability Of Protein-ligand Complexes Research Articles

Targeting decaprenylphosphoryl-β-D-ribose 2'-epimerase for Innovative Drug Development Against Mycobacterium Tuberculosis Drug-Resistant Strains.

Tuberculosis (TB) remains a global health challenge with the emergence of drug-resistant Mycobacterium tuberculosis variants, necessitating innovative drug molecules. One potential target is the cell wall synthesis enzyme decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1), crucial for virulence and survival. This study employed virtual screening of 111 Protein Data Bank (PDB) database molecules known for their inhibitory biological activity against DprE1 with known IC50 values. Six compounds, PubChem ID: 390820, 86287492, 155294899, 155522922, 162651615, and 162665075, exhibited promising attributes as drug candidates and validated against clinical trial inhibitors BTZ043, TBA-7371, PBTZ169, and OPC-167832. Concurrently, this research focused on DprE1 mutation effects using molecular dynamic simulations. Among the 10 mutations tested, C387N significantly influenced protein behavior, leading to structural alterations observed through root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), and solvent-accessible surface area (SASA) analysis. Ligand 2 (ID: 390820) emerged as a promising candidate through ligand-based pharmacophore analysis, displaying enhanced binding compared with reference inhibitors. Molecular dynamic simulations highlighted ligand 2's interaction with the C387N mutation, reducing fluctuations, augmenting hydrogen bonding, and influencing solvent accessibility. These collective findings emphasize ligand 2's efficacy, particularly against severe mutations, in enhancing protein-ligand complex stability. Integrated computational and pharmacophore methodologies offer valuable insights into drug candidates and their interactions within intricate protein environments. This research lays a strategic foundation for targeted interventions against drug-resistant TB, highlighting ligand 2's potential for advanced drug development strategies.

Enumeration of olive derived lignan, pinoresinol for activity against recent Omicron variant spike protein for structure-based drug design, DFT, molecular dynamics simulations, and MMGBSA studies.

The coronavirus disease 2019 (COVID-19) was first found in Wuhan, China, in December 2019. Because the virus spreads quickly, it quickly became a global worry. Coronaviridae is the family that contains both SARS-CoV-2 and the viruses that came before (i.e., MERS-CoV and SARS-CoV). Recent sources portray that the COVID-19 virus has affected 344,710,576 people worldwide and killed about 5,598,511 people in the last 2years. The B.1.1.529 strain, later called "Omicron," was named a Variant of Concern on November 24, 2021. The SARS-CoV-2 virus has gone through a never-ending chain of changes that have never happened before. As a result, it has many different traits. Most of these changes have occurred in the spike protein, where antibodies bind. Because of these changes, the Omicron type is very contagious and easy to pass on. There have been a lot of studies done to try to figure out this new challenge in the COVID-19 strains race, but there is still a lot that needs to be explained. This study focuses on virtual screening, docking, and molecular dynamic analysis; we aimed to identify therapeutic candidates for the SARS-CoV-2 variant Omicron based on their ability to inhibit non-structural proteins. We investigate the prediction of the properties of a substantial database of drug molecules obtained from the OliveNet™ database. Compounds that did not exhibit adequate gastrointestinal absorption and failed the Lipinski test are not considered for further research. The filtered compounds were coupled with our primary target, SARS-CoV-2 Omicron spike protein. We focused on SARS-CoV-2 Omicron spike protein and filtering potent olive compounds. Pinoresinol, the most likely candidate, is bound best (- 8.5kcal/mol). Pinoresinol's strong interaction with the active site made the complex's dynamic structure more resilient. MD simulations explain the protein-ligand complex's stability and function. Pinoresinol may be a promising SARS-CoV-2 Omicron spike protein receptor lead drug, and additional research may assist the scientific community.

Natural compound targeting BDNF V66M variant: insights from in silico docking and molecular analysis.

Brain-Derived Neurotrophic Factor (BDNF) is a neurotrophin gene family gene that encodes proteins vital for the growth, maintenance, and survival of neurons in the nervous system. The study aimed to screen natural compounds against BDNF variant (V66M), which affects memory, cognition, and mood regulation. BDNF variant (V66M) as a target structure was selected, and Vitamin D, Curcumin, Vitamin C, and Quercetin as ligands structures were taken from PubChem database. Multiple tools like AUTODOCK VINA, BIOVIA discovery studio, PyMOL, CB-dock, IMOD server, Swiss ADEMT, and Swiss predict ligands target were used to analyze binding energy, interaction, stability, toxicity, and visualize BDNF-ligand complexes. Compounds Vitamin D3, Curcumin, Vitamin C, and Quercetin with binding energies values of - 5.5, - 6.1, - 4.5, and - 6.7 kj/mol, respectively, were selected. The ligands bind to the active sites of the BDNF variant (V66M) via hydrophobic bonds, hydrogen bonds, and electrostatic interactions. Furthermore, ADMET analysis of the ligands revealed they exhibited sound pharmacokinetic and toxicity profiles. In addition, an MD simulation study showed that the most active ligand bound favorably and dynamically to the target protein, and protein-ligand complex stability was determined. The finding of this research could provide an excellent platform for discovering and rationalizing novel drugs against stress related to BDNF (V66M). Docking, preclinical drug testing and MD simulation results suggest Quercetin as a more potent BDNF variant (V66M) inhibitor and forming a more structurally stable complex.

Targeting SARS-CoV-2 main protease (Mpro) and human ACE-2: A virtual screening of carotenoids and polyphenols from tomato (Solanum lycopersicum L.) to combat Covid-19

BackgroundHuman angiotensin-converting enzyme-2 (ACE-2) and severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) main protease (Mpro) have been established as the prime targets to restrict viral invasion and replication inside the host, respectively. MethodsThe current study delineated the SARS-CoV-2 Mpro as well as human ACE-2 inhibitory potential of carotenoids and polyphenols from tomato (Solanum lycopersicum L.) via in-silico interaction studies. ResultsOur drug-likeness studies showed that the selected carotenoids and polyphenols exhibited acceptable Lipinski’s score and ADME determinants. Further, in-silico molecular modelling studies revealed that β-carotene, among other carotenoids, topped the binding score (ΔG: −6.75 ​kcal/mol; Ki: 11.32 ​μM) against SARS-CoV-2 Mpro, whereas, cyanidin was the best inhibitor of SARS-CoV-2 Mpro (−7.24 ​kcal/mol; Ki: 4.92 ​μM) amongst polyphenols. Similarly, α-carotene from carotenoids exhibited strongest human ACE-2 inhibitory activity (ΔG: −8.85 ​kcal/mol; Ki: 326.13 ​μM), whereas, cyanidin from polyphenols showed best binding affinity against human ACE-2 (ΔG: −7.24 ​kcal/mol; Ki: 4.89 ​μM). In contrast, 6-(ethylamino)-pyridine-3-carbonitrile, standard inhibitor of SARS-CoV-2 Mpro, exhibited comparatively weaker binding (ΔG: −4.78 ​kcal/mol; Ki: 267.49 ​μM), whereas, telmisartan (reference ACE-2 inhibitor) also exhibited lesser affinity (ΔG: −6.40 ​kcal/mol; Ki: 20.40 ​μM). Further exploration via MDS studies also validated the dynamic behavior and stability of protein-ligand complexes as evident by desirable RMSD, RMSF, Rg, and SASA. ConclusionThe current study established carotenoids and polyphenols from S. lycopersicum L. as finer substitutes of reference standards against SARS-CoV-2 Mpro and human ACE-2 activity in combating SARS-CoV-2 infection.

Therapeutic potential of dietary phytochemicals from Drynaria quercifolia to modulate gut microbiome: an in silico approach

Drynaria quercifolia is one of the pioneer medicinal plants which exert many beneficial effects on humans. Fatty acids are hydrophobic ligands that act as membrane substrates, metabolic signalling molecules, and metabolic energy sources. It could enhance the mucus production in the intestine which maintain mucosal homeostasis. The inflammatory responses were also regulated by 5-HT receptors. Serotonin 2 A receptors are G-protein coupled receptors targeted by various types of ligands viz. antidepressants, antipsychotics and anti-migraine drugs. The interaction of mucin protein and fatty acid could increase the antimicrobial activity and anti-inflammatory activity of gut microbiome. In this study, dietary phytochemicals were extracted from D. quercifolia and characterized using GC-MS analysis. The result shows presence of 38 various compounds viz. decanoic acid, indole, and dodecanoic acid and etc., Among the all, dodecanoic acid showed good drug likeness and pharmaceutical properties. Target proteins viz. 3IFB (Intestinal fatty acid binding protein) and 7WC4 (5-hydroxytryptamine receptor 2 A) were docked with dodecanoic acid using Auto dock software. The fatty acids produced in the gut could interact with 3IFB and 7WC4 proteins to maintain intestinal integrity and improved gut-brain function respectively. Dodecanoic acid exhibits the highest binding energy with mutated 3IFB (-6.01) than native whereas 7WC4 native protein showed (-7.3 kal/mol) the highest affinity than mutated protein. Structural changes were predicted by using SOPMA and ProSA. Evaluation results indicate that 3IFB was having more stability, good quality, and enhanced affinity than 7WC4. Further, MD simulations were done for 3IFB to check the stability of protein-ligand complex using WebGro platform. The model was investigated by root mean square deviation and fluctuations. Therefore, dodecanoic acids have been considered as a potential agonists and offer opportunities for developing innovative medications for gastrointestinal diseases. Communicated by Ramaswamy H. Sarma

In silico ADMET, toxicological analysis, molecular docking studies and Molecular dynamics simulation of Afzelin with potential antibacterial effects against Staphylococcus aureus

Afzelin has been designed and tested for its in silico antibacterial activity against DNA gyrase complex of Staphyloccocus aureus. The results of the toxicity study indicate that afzelin displayed moderate antibacterial potential against staphylococcus aureus with LD50 = 5000 mg/Kg, which is almost four times and a half weaker than that obtained for the commercial antibiotic chloramphenicol. The afzelin and the commercial antibiotic chloramphenicol were subjected to docking studies to understand their interaction with DNA gyrase complex of Staphyloccocus aureus. Results indicated a good affinity of afzelin to the chosen target with the formation of four hydrogen bonds and binding energy of 29.82 KJ/mol. ADME study shows that afzelin is not inhibitors of CYP450 IA2, 2C19, 2C9, 2D6, 3A4 isoenzymes which suggests a decrease in their plasma concentrations and a rapid elimination route. Molecular dynamics simulations were performed for 10 ns for afzelin using the gromacs package to assess the conformational stability of protein-ligand complexes during the simulation.

Structure based exploration of potential lead molecules against the extracellular cysteine protease (EcpA) of Staphylococcus epidermidis: a therapeutic halt

Nosocomial infection caused by Staphylococcus epidermidis is one of the most widely spread diseases affecting the world’s population. No strategies have been developed to overcome this infection and inhibit its spread in immunocompromised patients or patients with indwelling medical devices. EcpA is an extracellular cysteine protease protein involved in biofilm formation on medical devices. Thus, blocking this mechanism may be viable for developing a drug against S. epidermidis. The current research aimed to find new, potent inhibitors that could stop the S. epidermidis EcpA protein from functioning. This study attempted to identify the most promising drug candidates using structure-based virtual screening (SBVS) from libraries of natural ligands. The top-scored molecules were shortlisted based on their IC50 values and pharmacophore properties and further validated through density functional theory (DFT) studies. We found five inhibitors using virtual screening, and the results indicate that these drugs had the highest energy binding potential towards the EcpA targets when compared to the reference molecule E-64, a known cysteine protease inhibitor. In order to evaluate the binding conformational stability of protein-ligand complexes, molecular dynamics (MD) simulations were performed in triplicate for 100 ns, revealing the significant stability of anticipated molecules at the docked site. Furthermore, principal component analysis and binding free energy calculations were performed to understand the dynamics and stability of the complexes. The current study indicated that these compounds looked to be suitable novel inhibitors of the EcpA protein and pave the path for further discovery of novel inhibitors of EcpA. Communicated by Ramaswamy H. Sarma

Identification of the Seaweed Metabolites as Potential Anti-tubercular Agents Against Human Pantothenate synthetase: An In Silico Approach.

Tuberculosis is the disease which is caused due to the contagion of Mycobacterium tuberculosis. The multidrug resistance Mycobacterium tuberculosis is the main hassle in the treatment of this worldwide health threats. Pantothenate synthase is a legitimate goal for rational drug designing against Mycobacterium tuberculosis. The enzyme is most active in the presence of magnesium or manganese. Marine algal cell wall is rich in sulfated polysaccharides such as fucoidans (brown algae), κ-carrageenans (red algae), and ulvan (green algae) with various favorable biological activities such as anticoagulant, antiviral, antioxidative, anticancer, and immunomodulating activities. In this study, we have modeled binding modes of selected known anti-tubercular compounds and different solvent extract against pantothenate synthase using advanced docking program AutoDock 4.2 tool. In our current study, in silico experiments were carried out to determine if fucoidan, κ-carrageenan, and ulvan sulfated polysaccharides could be a potential target against PANc (pantothenate synthetase), with the goal of identifying potential inhibitors as anti-TB leads targeting PANc for further wet lab validation. Two bioactive compounds were docked to the Mtb pantothenate synthetase protein binding site, with docking scores ranging from -5.57 to -2.73. κ-carrageenan had the best pose and docking score, with a Ligand fit score of -5.815. Ulvan did not dock with the protein. The molecular dynamics simulations were conducted with substrate and ligand bounded fucoidan and κ-carrageenan for 150ns and the protein Mtb pantothenate synthetase showed a stable conformation in the simulation, with tight amino acid contributions binding to the ligand molecule. RMSD characterizes the conformation and stability of protein ligand complexes, with higher fluctuations indicating low stability and minimal low-level fluctuations indicating equilibration and stability. The graph for RMSF shows significant peaks due to fluctuations in active site regions and other peaks indicating the adaptation of the ligand molecule to the protein binding pocket. From the molecular dynamics study, it is clear that the compounds are having good binding affinity in the active site. The root mean square deviation, root mean square fluctuations, and radius of gyration are supportive evidences which helped us to conclude that the compounds κ-carrageenan and fucoidan are suitable lead molecules for inhibiting pantothenate synthetase. Based on these evidences, the natural compounds from seaweeds can be tested clinically either alone or in combinations against the protein, which could facilitate the designing or the synthesis of new lead molecules as drugs against the tuberculosis.

Valorization of Kappaphycus alvarezii through extraction of high-value compounds employing green approaches and assessment of the therapeutic potential of κ-carrageenan

This study utilizes different emerging green extraction technologies to recover maximum value-added products from Kappaphycus alvarezii and evaluate their bio-functional properties. Using the supercritical fluid extraction (SFE) method, the total lipid yield of 0.21 ± 0.2 % was obtained from the biomass. Linoleic acid, eicosapentaenoic acid, arachidonic acid, γ-linolenic acid, and docosahexaenoic acid were present in higher concentrations (9.12 %) in the lipid extracted with SFE as compared to hexane (5.5 %). Using an ultrasonication assisted approach, ~56 % of κ-carrageenan was recovered from SFE residual biomass, which contains 28.5 ± 1.9 % sulfate content. It exhibited a monosaccharide content of 3,6-anhydrogalactose (~24 %) and galactose (~53 %), as well as rheological properties within FAO limitations that can be explored for food-grade applications. ~58 % of the total protein (12.5 %) from SFE residual biomass was recovered using subcritical water hydrolysis method. The effectiveness of κ-carrageenan in suppressing the 3CLpro of SARS-CoV-2 using in vitro and in silico approaches was investigated. κ-Carrageenan effectively inhibited the main protease by up to 93 % at 1.6 mg mL−1. In silico results revealed that κ-carrageenan successfully binds to the active site of the main protease while retaining the structural integrity and stability of protein-ligand complexes.

An in silico molecular docking, ADMET and molecular dynamics simulations studies of azolyl-2H-chroman-4-ones as potential inhibitors against pathogenic fungi and bacteria

Antimicrobial resistance is a major global threat. In an attempt to discover new compounds with improved efficiency and to overcome drug resistance, a library of 3960 compounds was designed as conformationally rigid analogues of oxiconazole with 2H-chroman-4-one, azole and substituted phenyl fragments. The antifungal and antibacterial activity of the compounds was evaluated using molecular docking studies in the active site of six fungal and four bacterial proteins to establish the binding affinity of the designed ligands. In-silico ADME and Lipinski’s rule were used to establish the drug-likeness properties of the compounds. This study revealed that all the designed compounds had a high binding affinity with the target proteins and formed H-bond and π-π interactions. The identified hits have been subjected to molecular dynamics simulations to study protein-ligand complex stability. This study has led to the identification of important compounds that can be developed further as therapeutic agents against pathogenic fungi and bacteria. Communicated by Ramaswamy H. Sarma

Synthesis, spectroscopic investigations, topological non-covalent interactions, chemical reactivity, molecular docking and molecular dynamic simulation on piperazine succinate - A potential antimicrobial compound

Piperazine Succinate (PZSN) has been synthesized and extensively analyzed using various spectroscopic techniques, including FT-IR, FT-Raman and NMR spectra. In optimizing geometry, a comparison between the bond lengths of C2-H25 in PZSN (1.0999 Å) and SN (1.0938 Å) reveals an increase of 0.0061 Å in the C21-H25 bond length for PZSN. This elongation can be attributed to the significant C21-H25‧‧‧N2 intermolecular hydrogen bonding interaction. Natural bond orbital analysis of the molecule indicates a significant charge transfer between LP(1) N2 → σ* (C21-H25) leads to a substantial stabilization energy of 6.73 kcal/mol, providing strong evidence for the presence of intermolecular hydrogen bonding interactions. The strong band observed in the IR spectrum at 3510 cm−1, assigned to N2-H16 stretching mode, which clearly supports the formation of a hydrogen bond between succinate C=O and piperazine NH group. The complete vibrational assignments and the force constants has been reported for PZSN by using B3LYP/6–311++G** method. Molecular parameters, such as Frontier Molecular Orbital (FMO) energies, Fukui functions and Molecular Electrostatic Potential (MEP), have been calculated to gain insights into the stability and reactivity of the molecule. According to the QTAIM analysis, the presence of a strong non-bonded interaction is supported by the largest interaction energy observed at the C21-H25‧‧‧N2 bond critical point (BCP), which is 3.42 kcal/mol. Furthermore, Reduced Density Gradient (RDG) and Independent Gradient Model (IGM) approaches have been performed to disclose the attractive contacts like hydrogen bonds, repulsive and van der Waals interconnections. The molecule's drug-likeness has been assessed using Lipinski's rule and ADMET contour analysis indicated its potential for pharmaceutical applications. Molecular docking modeling have been conducted on antimicrobial proteins to explore the structure-activity relationship and antimicrobial testing confirmed the molecule's efficacy against microbial infections. Molecular dynamic simulations have been utilized to examine the stability of protein-ligand complex.

A computational study to identify Sesamol derivatives as NRF2 activator for protection against drug-induced liver injury (DILI).

Drug-induced liver injury can be caused by any drugs, their metabolites, or natural products due to the inefficient functioning of drug-metabolizing enzymes, resulting in reactive oxygen species generation and leading to oxidative stress-induced cell death. For protection against oxidative stress, our cell has various defense mechanisms. One of the mechanisms is NRF2 pathway, when activated, protects the cell against oxidative stress. Natural antioxidants such as Sesamol have reported pharmacological activity (hepatoprotective & cardioprotective) and signaling pathways (NRF2 & CREM) altering potential. A Computational analysis was done using molecular docking, IFD, ADMET, MM-GBSA, and Molecular dynamic simulation of the Schrödinger suite. A total of 63,345 Sesamol derivatives were downloaded for the PubChem database. The protein structure of KEAP1-NRF2 (PDB: 4L7D) was downloaded from the RCSB protein database. The molecular docking technique was used to screen compounds that can form an interaction similar to the co-crystalized ligand (1VX). Based on MM-GBSA, docking score, and interactions, ten compounds were selected for ADMET profiling and IFD. After IFD, five compounds (66867225, 46148111, 12444939, 123892179, & 94817569) were selected for molecular dynamics simulation (MDS). Protein-ligand complex stability was assessed during MDS. The selected compounds (66867225, 46148111, 12444939, 123892179, & 94817569) complex with KEAP1 protein shows good stability and bond retentions. In our study, we observed that the selected compounds show good interaction, PCA, Rg, binding free energy, and ADMET profile. We can conclude that the selected compounds can act as NRF2 activators, which should be validated using proper in-vivo/in-vitro models.

Molecular modeling and biological investigation of novel s-triazine linked benzothiazole and coumarin hybrids as antimicrobial and antimycobacterial agents

A novel series of s-triazine linked benzothiazole and coumarin hybrids (6a-6d, 7a-7d, and 8a-8d) were synthesized and characterized by IR, NMR, and mass spectrometry. The compound’s in vitro antibacterial and antimycobacterial activities were also evaluated. Remarkable antibacterial activity with MIC in the range of 12.5–62.5 μM and antifungal activity of 100–200 μM were demonstrated by in vitro antimicrobial analysis. Compounds 6b, 6d, 7b, 7d, and 8a strongly inhibited all bacterial strains, while 6b, 6c, and 7d had good to moderate efficacy against M. tuberculosis H37Rv. Synthesized hybrids are observed in the active pocket of the S. aureus dihydropteroate synthetase enzyme, according to a molecular docking investigations. Among the docked compounds, 6d had a strong interaction and a greater binding affinity, and the dynamic stability of protein-ligand complexes was examined using molecular dynamic simulation with various settings at 100 ns. The proposed compounds successfully maintained their molecular interaction and structural integrity inside the S. aureus dihydropteroate synthase, according to the MD simulation analysis. These in silico analyses supported the in vitro antibacterial results of compound 6d, which demonstrated outstanding in vitro antibacterial efficacy against all bacterial strains. In the quest for new antibacterial drug-like molecules, compounds 6d, 7b, and 8a have been identified as promising lead compounds. Communicated by Ramaswamy H. Sarma

Development of novel chromones as antioxidant COX2 inhibitors: in vitro, QSAR, DFT, molecular docking, and molecular dynamics studies

The chromone derivatives are playing a prominent role in many plant cycles, for instance, the regulation of growth, stimulation of oxygen uptake in plants, and essential food constituents with valuable pro-health properties. Determination of the antioxidant activity of these compounds is an interesting approach to drug design and development. The antioxidant activity of the novel fifteen chromone compounds was estimated by using a spectrophotometric Dichloro-5,6-dicyano 1,4-benzoquinone (DDQ) assay method and the mechanism of antioxidant activity was discussed based on the Density functional theory (DFT) calculations. The compounds showed significant antioxidant activity which was correlated to their molecular structure by considering various molecular descriptors. Further, by using regression analysis QSAR-modeled equation was proposed and it has shown a high correlation coefficient value (0.946. We perform molecular docking and molecular dynamics simulations against the cyclooxygenase (COX2) enzyme to investigate the molecule’s anti-inflammatory activity and stability of protein-ligand complexes. Molecular docking and dynamics simulations revealed the compounds B3 and B8 were interacting with essential residues TYR385, HIS386, ASN382, TRP387, and HIS388 in the binding site that were crucial for optimizing heme and the resultant peroxidase and cyclooxygenase activities. The root mean square displacement and root mean square fluctuation plots revealed the stability of the B3-COX2 and B8-COX2 complexes. Based on our results, B3 and B8 compounds are considered as best antioxidants as well as COX2 inhibitors. Communicated by Ramaswamy H. Sarma

Translational protein RpsE as an alternative target for novel nucleoside analogues to treat MDR Enterobacter cloacae ATCC 13047: network analysis and molecular dynamics study

The pathogenic Enterobacter cloacae subsp. cloacae str. ATCC 13047 has contemporarily emerged as a multi-drug resistant strain. To formulate an effective treatment option, alternative therapeutic methods need to be explored. The present study focused on Gene Interaction Network study of 46 antimicrobial resistance genes to reveal the densely interconnecting and functional hub genes in E. cloacae ATCC 13047. The AMR genes were subjected to clustering, topological and functional enrichment analysis, revealing rpsE (RpsE), acrA (AcrA) and arnT (ArnT) as novel therapeutic drug targets for hindering drug resistance in the pathogenic strain. Network topology further indicated translational protein RpsE to be exploited as a promising drug-target candidate for which the structure was predicted, optimized and validated through molecular dynamics simulations (MDS). Absorption, distribution, metabolism and excretion screening recognized ZINC5441082 (N-Isopentyladenosine) (Lead_1) and ZINC1319816 (cyclopentyl-aminopurinyl-hydroxymethyl-oxolanediol) (Lead_2) as orally bioavailable compounds against RpsE. Molecular docking and MDS confirmed the binding efficacy and protein-ligand complex stability. Furthermore, binding free energy (Gbind) calculations, principal component and free energy landscape analyses affirmed the predicted nucleoside analogues against RpsE protein to be comprehensively examined as a potential treatment strategy against E. cloacae ATCC 13047.

Computational studies, synthesis, in-vitro binding and transcription analysis of novel imidazolidine-2,4‑dione and 2-thioxo thiazolidine-4-one based glitazones for central PPAR-γ agonism

Herein, we describe the structure-based designing and synthesis of novel glitazones with imidazolidine 2, 4‑dione and 2-thioxo thiazolidine-4-one ring structures as the fundamental scaffold for central PPAR-γ binding and activation. The central activation of PPAR-γ/coactivator PGC-1α induces a beneficial effect in neurodegenerative disorders. The compounds were rationally designed with particular emphasis on toxicity parameters and subjected to computational screening. Totally, four compounds were selected from an in-house library of designed glitazones based on imidazolidine 2, 4‑dione and 2-thioxo thiazolidine-4-one ring structures for further investigation for PPAR-γ activation. Molecular docking of designed glitazones with PPAR-γ proteins revealed more binding affinity with hydrogen bond interaction of protein residue at Ser289, His323, Tyr327, and Tyr473 compared with standard Pioglitazone. The structural stability of protein-ligand complexes was confirmed by molecular dynamic (MD) simulation (100 ns), and results indicate significant interactions with PPAR-γ active sites. Additionally, the relationship between geometry and electronic properties of chemical compounds were investigated using HOMO-LUMO, MEP, and NBO analysis. The compounds were synthesized by established synthetic schemes and structurally analyzed using IR, 1H NMR, 13C NMR and mass spectral analysis. The binding affinity of the compounds with the target protein (PPAR-γ) was further confirmed by an in vitro competitive binding assay with values ranging from 0.951μM- 4.768 μM. TR-FRET binding assay also concluded the ability of the novel compounds G5 and G7 to bind specifically at the LBD of PPAR-γ. Among the developed glitazones, the compound G7 activates PPAR-γ in a dose-dependent manner in transcriptional assay. Our results also indicated that compounds G5 and G7 exhibit nontoxicity (IC50>120 μM) against the SH-SY5Y cell lines and both could be a most bioactive lead candidates for further investigations.

Identification of RdRp inhibitors against SARS-CoV-2 through E-pharmacophore-based virtual screening, molecular docking and MD simulations approaches

The outbreak of novel Coronavirus, an enduring pandemic declared by WHO, has consequences to an alarming ongoing public health menace which has already claimed several million human lives. In addition to numerous vaccinations and medications for mild to moderate COVID-19 infection, lack of promising medication or therapeutic pharmaceuticals remains a serious concern to counter the ongoing coronavirus infections and to hinder its dreadful spread. Global health emergencies have called for urgency for potential drug discovery and time is the biggest constraint apart from the financial and human resources required for the high throughput drug screening. However, computational screening or in-silico approaches appeared to be an effective and faster approach to discover potential molecules without sacrificing the model animals. Accumulated shreds of evidence on computational studies against viral diseases have revealed significance of in-silico drug discovery approaches especially in the time of urgency. The central role of RdRp in SARS-CoV-2 replication makes it promising drug target to curtain on going infection and its spread. The present study aimed to employ E-pharmacophore-based virtual screening to reveal potent inhibitors of RdRp as potential leads to block the viral replication. An energy-optimised pharmacophore model was generated to screen the Enamine REAL DataBase (RDB). Then, ADME/T profiles were determined to validate the pharmacokinetics and pharmacodynamics properties of the hit compounds. Moreover, High Throughput Virtual Screening (HTVS) and molecular docking (SP & XP) were employed to screen the top hits from pharmacophore-based virtual screening and ADME/T screen. The binding free energies of the top hits were calculated by conducting MM-GBSA analysis followed by MD simulations to determine the stability of molecular interactions between top hits and RdRp protein. These virtual investigations revealed six compounds having binding free energies of −57.498, −45.776, −46.248, −35.67, −25.15 and −24.90 kcal/mol respectively as calculated by the MM-GBSA method. The MD simulation studies confirmed the stability of protein ligand complexes, hence, indicating as potent RdRp inhibitors and are promising candidate drugs to be further validated and translated into clinics in future.

Ginger ring compounds as an inhibitor of spike binding protein of alpha, beta, gamma and delta variants of SARS-CoV-2: An in-silico study.

The available drugs against coronavirus disease 2019 (COVOD-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are limited. This study aimed to identify ginger-derived compounds that might neutralize SARS-CoV-2 and prevent its entry into host cells. Ring compounds of ginger were screened against spike (S) protein of alpha, beta, gamma, and delta variants of SARS-CoV-2. The S protein FASTA sequence was retrieved from Global Initiative on Sharing Avian Influenza Data (GISAID) and converted into ".pdb" format using Open Babel tool. A total of 306 compounds were identified from ginger through food and phyto-databases. Out of those, 38 ring compounds were subjected to docking analysis using CB Dock online program which implies AutoDock Vina for docking. The Vina score was recorded, which reflects the affinity between ligands and receptors. Further, the Protein Ligand Interaction Profiler (PLIP) program for detecting the type of interaction between ligand-receptor was used. SwissADME was used to compute druglikeness parameters and pharmacokinetics characteristics. Furthermore, energy minimization was performed by using Swiss PDB Viewer (SPDBV) and energy after minimization was recorded. Molecular dynamic simulation was performed to find the stability of protein-ligand complex and root-mean- square deviation (RMSD) as well as root-mean-square fluctuation (RMSF) were calculated and recorded by using myPresto v5.0. Our study suggested that 17 out of 38 ring compounds of ginger were very likely to bind the S protein of SARS-CoV-2. Seventeen out of 38 ring compounds showed high affinity of binding with S protein of alpha, beta, gamma, and delta variants of SARS-CoV-2. The RMSD showed the stability of the complex was parallel to the S protein monomer. These computer-aided predictions give an insight into the possibility of ginger ring compounds as potential anti-SARS-CoV-2 worthy of in vitro investigations.

Synthesis, characterization, molecular dynamic simulation, and biological assessment of cinnamates linked to imidazole/benzimidazole as a CYP51 inhibitor

A class of 2-(1H-imidazol-1-yl)-1-phenylethyl cinnamates 6a-6j and 2-(1H-benzo[d]imidazol-1-yl)-1-phenylethyl cinnamates 7a-7j were synthesized, and their synthesis was validated using various spectroscopic techniques like IR, NMR, and Mass spectrometry. In addition, the compounds were assessed for in-vitro antibacterial against gram-positive and gram-negative strains and in-vitro antifungal against six different fungal strains. Compounds 6 g, 7 b, 7f, and 7 g exhibited significant activity against all bacterial strains ranging from MIC = 12.5-50 µg/mL, and compounds 6 g, 7 b, and 7 g exhibited considerable activity against all fungal strains ranging from MFC = 125-200 µg/mL. A molecular docking study indicated that compounds 6 g, 7 b, 7 g, and 7j could be lodged in the active pocket and inhibit C. albicans Sterol 14α-demethylase (CYP51) protein via various interactions, and these studies validate the antifungal results. Different parameters from the 100 ns MD simulation study are investigated to evaluate the dynamic stability of protein-ligand complexes. According to the MD simulation study, the proposed compounds effectively kept their molecular interaction and structural integrity within the C. albicans Sterol 14-demethylase. Compounds 6 g, 7 b, and 7 g are promising lead compounds in searching for novel antifungal drug-like molecules. Furthermore, in silico ADME indicates that these compounds possess drug-like physicochemical properties to be orally bioavailable. Communicated by Ramaswamy H. Sarma

Highlights in TMPRSS2 inhibition mechanism with guanidine derivatives approved drugs for COVID-19 treatment

Transmembrane protease serine 2 (TMPRSS2) has been identified as a critical key for the entry of coronaviruses into human cells by cleaving and activating the spike protein of SARS-CoV-2. To block the TMPRSS2 function, 18 approved drugs, containing the guanidine group were tested against TMPRSS2’s ectodomain (7MEQ). Among these drugs, Famotidine, Argatroban, Guanadrel and Guanethidine strongly binds with TMPRSS2 S1 pocket with estimated Fullfitness energies of −1847.12, −1630.87, −1605.81 and −1600.52 kcal/mol, respectively. A significant number of non-covalent interactions such as hydrogen bonding, hydrophobic and electrostatic interactions were detected in protein-ligand complexes. In addition, the ADMET analysis revealed a perfect concurrence with the aptitude of these drugs to be developed as an anti-SARS-CoV-2 therapeutics. Further, MD simulation and binding free energy calculations were performed to evaluate the dynamic behavior and stability of protein-ligand complexes. The results obtained herein highlight the enhanced stability and good binding affinities of the Argatroban and Famotidine towards the target protein, hence might act as new scaffolds for TMPRSS2 inhibition. Communicated by Ramaswamy H. Sarma