PDB ID Research Articles

Series of Novel Integrastatins Analogues: In silico Study of Physicochemical and Bioactivity Parameters

Integrastatins are naturally occurring heterotetracyclic compounds with a broad spectrum of biological activity. A number of new structural analogues of integrastatins 2a-u have been synthesized using a novel one-step method [1], but a systematic theoretical study of their structural features and biological activity has not been realized. This study aimed to in silico investigate physicochemical and bioactivity properties for a series of 21 new synthetic analogues of natural integrastatins. Global chemical reactivity descriptors was assessed using DFT B3LYP 6-311++G(d, p) CPCM (solvent — water) calculations. High ionization potential IP in the range from 5.9 to 7.1 eV and electron affinity EA at the level of 2.1 to 3.2 eV were shown, which together with a sufficiently large energy gap DEgap from 3.8 to 4.6 eV indicates the hard nature of the compounds 2a-u. Antiviral activity and inhibitory potential as CYP2C19 inducers were identified using the PASSOnline resource. According to the results of molecular docking studies Human immunodeficiency virus HIV-1 reverse transcriptase protein (PDB ID: 3V81) and protein of the RNA-dependent RNA polymerase of the SARS-CoV-2 (PDB ID: 7AAP) can serve as a likely biological target for the compounds 2a-u. Potentially high oral efficacy and a promising safety profile for the therapeutic use were showed using ADMETlab 3.0 online portal. Further experimental in vitro and in vivo studies of the pharmaceutical potential of compounds 2a-u is need for more accurate evaluation the assumptions made on the basis of in silico approach.

Discovery of Potent Dengue Virus NS2B-NS3 Protease Inhibitors Among Glycyrrhizic Acid Conjugates with Amino Acids and Dipeptides Esters

This study investigated a library of known and novel glycyrrhizic acid (GL) conjugates with amino acids and dipeptide esters, as inhibitors of the DENV NS2B-NS3 protease. We utilized docking algorithms to evaluate the interactions of these GL derivatives with key residues (His51, Asp75, Ser135, and Gly153) within 10 Å of the DENV-2 NS2B-NS3 protease binding pocket (PDB ID: 2FOM). It was found that compounds 11 and 17 exhibited unique binding patterns, forming hydrogen bonds with Asp75, Tyr150, and Gly153. Based on the molecular docking data, conjugates 11 with L-glutamic acid dimethyl ester, 17 with β-alanine ethyl ester, and 19 with aminoethantic acid methyl ester were further demonstrated as potent inhibitors of DENV-2 NS3 protease, with IC50 values below 1 μM, using NS3-mediated cleavage assay. Compound 11 was the most potent, with EC50 values of 0.034 μM for infectivity, 0.042 μM for virus yield, and a selective index over 2000, aligning with its strong NS3 protease inhibition. Compound 17 exhibited better NS3 protease inhibition than compound 19 but showed weaker effects on infectivity and virus yield. While all compounds strongly inhibited viral infectivity post-entry, compound 19 also blocked viral entry. This study provided valuable insights into the interactions between active GL derivatives and DENV-2 NS2B-NS3 protease, offering a comprehensive framework for identifying lead compounds for further drug optimization and design as NS2B-NS3 protease inhibitors against DENV.

Molecular Docking and Molecular Dynamics Simulations of Molnupiravir Against Covid-19

The most stable conformation of molnupiravir (C13H19N3O7), which is frequently used in the COVID-19 treatment, was elucidated by the Spartan06 program. Using the CAVER program, the potential active binding sites that belong to the spike glycoprotein, ACE2 receptor, and both the apo and holo forms of the main protease enzyme(Mpro) of COVID-19 were identified. To determine the binding affinity of molnupiravir to target receptors, molecular docking analyses were carried out using Autodock Vina. The results of molecular docking calculations of the molnupiravir with the spike glycoprotein (PDB ID:6VXX), ACE2 (PDB ID:6M0J;1R42), the apo form (PDB ID: 6M03) and the holo form of COVID-19 Mpro (PDB ID: 6LU7) showed strong binding affinities at -7.8, -7.7, -7.7, -7.1, and -7.4 kcal/mol, respectively. Moreover, top-scoring ligand-receptor complex of the molnupiravir with ACE2 (1R42) were subjected to 50 ns all-atom MD simulations to investigate the ligand-receptor interactions in more detail.

Integration of pharmacophore-based virtual screening, molecular docking, ADMET analysis, and MD simulation for targeting EGFR: A comprehensive drug discovery study using commercial databases.

The epidermal growth factor receptor (EGFR), a crucial component of cellular signaling pathways, is frequently dysregulated in a range of cancers. EGFR targeting has become a viable approach in the development of anti-cancer medications. This study employs an integrated approach to drug discovery, combining multiple computational methodologies to identify potential EGFR inhibitors. The co-crystal ligand for the EGFR protein (R85) (PDB ID: 7AEI) was employed as a model for developing pharmacophore hypotheses. Nine databases underwent a ligand-based virtual screening, and 1271 hits meeting the screening criteria were chosen. EGFR protein crystal structure was obtained from the PDB database (PDB ID: 7AEI) and prepared. The hit compounds identified during virtual screening were docked to the prepared EGFR receptor to predict binding affinities by using the glide tool's standard precision mode. The top ten compounds were chosen, and their affinities of binding ranged from -7.691 to -7.338 kcal/mol. The ADMET properties of the selected compounds were predicted, and three compounds MCULE-6473175764, CSC048452634, and CSC070083626 showed better QPPCaco values compared to other identified compounds, so these were selected for further stability analysis. To confirm the stability of the protein-ligand complexes, a 200 ns molecular dynamics (MD) simulation was run using the binding sites of the top three compounds against the EGFR receptor. These results suggest that the selected compounds may be lead compounds in suppressing the biological activity of EGFR, additional experimental investigation is required.

Effect of Concentration of TiO2 Nanoparticles on Thiadiazole Derivative and Their Molecular Docking Study.

In the present work, we report the synthesis of TiO2 nanoparticles by hydrothermal method using titanium isopropoxide. The synthesized TiO2 nanoparticles were investigated by Powder X-ray diffraction, FE-SEM with EDX, Photoluminescence, UV-Visible absorption and Fluorescence emission spectroscopy. Fluorescence intensity and absorption values of 4-[5-(2,5-Dimethyl-pyrrol-1-yl)-[1,3,4]thiadiazol-2-ylsulfanylmethyl]-6-methoxy-chromen-2-one (DTYMC) molecule decreases with adding the concentration of TiO2 nanoparticles. Stern-Volmer equation for steady state method is found to be linear and its co-relation coefficient is found to be r = 0.88, which indicates the presence of dynamic quenching. Binding orientations of the DTYMC ligand with targeted proteins are Thymidylate synthase (TS) - PDB ID: 1JU6, The type II topoisomerases (TOP2α) - PDB ID: 4FM9 and Human thymidine phosphorylase (hTP) - PDB ID: 2WK6. The obtained result suggests that, the DTYMC molecule exhibits inhibitory activity against the overexpression of TS receptor which causes non-small cell lung cancer (NSCLC). Antimicrobial study of TiO2 NPs has been determined.

Green synthesis, anti-inflammatory evaluation and molecular docking of novel pyridines via one pot multi-component reaction using ultrasonic irradiation.

In this paper, we present a green application for the synthesis of novel pyridine derivatives 4a-f via one-pot, multicomponent reaction (MCRs) of some aromatic aldehydes 1a-f with malononitrile (2) and N-(4-acetylphenyl)-4-methylbenzenesulfonamide (3) in the presence of ammonium acetate using ultrasonic irradiation (U.S) in an aqueous solvent H2O:EtOH (2:1). The structures of all synthesized pyridines 4a-f were confirmed via elemental analysis and different spectroscopic techniques. This application has many advantages such as avoiding hazardous solvents, excellent yields, inexpensive, simple application, in addition to obtain pure compounds. The anti-inflammatory activity of the newly compounds was examined with the reference drug Ibuprofen. The obtained results showed that most derivatives are promising anti-inflammatory activates. Moreover, compound 4b exhibits the most anti-inflammatory activity with a percentage of inhibition with 51.67% compared with Ibuprofen 53.96%. Furthermore, the newly compounds were studied in their molecular docking simulations against the enzyme Human Cyclooxygenase-2, with Tolfenamic Acid as a reference ligand (PDB ID: 5IKT). Compound 4b demonstrated a robust binding affinity with the target protein 5ikt, evidenced by its binding affinity score of - 11.16 kcal/mol, which is the highest among the studied compounds.

O-Acetyl Bakuchiol exhibit Analgesic, Anti-inflammatory and Anti-arthritic effects: A combined in silico and in vivo experimental study.

In the present manuscript, we evaluated the analgesic, anti-inflammatory and anti-arthritic effects of bakuchiol derivative, O-Acetyl bakuchiol (BAc) at 5, 10 and 20 mg/kg p.o. dose in adult female Sprague Dawley rats.BAc at 20 mg/kg p.o. exhibited maximum analgesic (47.4%), anti-inflammatory (66.50%) and antiarthritic effects. Among the different parameters,BAc at 20 mg/kg increased the body weight (2.89%), decreased the paw thickness (72.46%)) and paw inflammation (48.59%) in FCA induced arthritic rats. In hematological/serum and biochemical parameters, BAc at 20 mg/kg brought the altered level of ESR, Hb, HCT, RBC, TLC and platelet count, HDL, cholesterol, triglycerides, CRP and RA factornear to the normal. Moreover, the spleen weight was also reduced in BAc treated rats at 20 mg/kg. Histopathological analysis further revealed that a reduction in paw inflammation was observed in paw ankle joints and no inflammation was observed in brain, liver, lungs and kidney in BAc treated rats at 20 mg/kg p.o. Molecular docking studies further revealed that BAc has better binding affinity for TNF-α (PDB ID: 7JRA) -7.19 kcal/mol comparable to standard methotrexate with binding affinity -9.56 kcal/mol. Therefore, the present investigation provided the basis for the development of BAc as potential candidate for the treatment of arthritis.

Monitoring the properties of 1,2,4-triazole derivatives for the development of original antimicrobial drugs

Aim. A comprehensive study on the antimicrobial properties of new 1,2,4-triazole derivatives using the tools of in silico and in vitro studies. Materials and methods. Computer search techniques were used to find a compound with a strong antibacterial activity; in silico molecular docking (receptors for class A (PDB id: 1n9b) and class A SHV-1 (PDB id: 2zd8) beta-lactamase) and in vitro studies on 16 types of microorganisms. Then, the in silico analyzed compounds were tested in vitro for antimicrobial activity. After preparing solutions of different concentrations, the culture growth was measured on a zonal scale for detecting sizes of microbial growth inhibition zones after 24 hours (Antibiotic Zone Scale-C, model RW297, India) and a TpsDig2 software (2016, F. James Rohlf). Statistical analysis of the study results was carried out using the Statistica 13 software (StatSoft Inc., USA). Results. From the results of molecular docking, a strong binding affinity to class A enzymes has been found in compounds 2, 7, so they could be effective in the treatment of infection caused by K. pneumoniae. The ascending order of the predicted binding affinity through the calculated score for TEM and SHV enzymes was as follows: compound 4 < compound 3 < compound 1 < compound 7 < compound 2. According to our results, the studied chemical compounds 1–4, 7 inhibited the growth of many microbial species of the Enterobacteriaceae, Morganellaceae, Pseudomonadaceae, Enterococcaceae, Staphylococcaceae and Bacillaceae families. Conclusions. For the first time, studies on the complex inhibitory effect of chemical compounds 1–4, 7 were conducted using 16 bacterial strains. Evident antibacterial effects of the studied compounds have been established: compound 1 against 13, compound 2 – 9, compound 3 – 10, compound 4 – 7, compound 7 – 10 out of 16 tested polyresistant bacterial strains.

Design and Synthesis of Novel Spiro [Chromane‐2,4′‐Piperidin]‐4‐One Derivatives: Anti‐Proliferative Investigation and Molecular Docking Studies

AbstractChemists around the globe are extensively working for remedial solutions to cancer, one of the greatest health hazards. We have synthesized twenty‐three novel spiro [chromane‐2,4′‐piperidin]‐ 4 ‐one derivatives (KBS and KMS series of analogues) as part of our ongoing research to combat this deadly disease, and confirmed their structures using 1H NMR, 13C NMR, HRMS, and FT‐IR. Furthermore, we employed single‐crystal XRD to identify the compound structures of KBS4 and KMS10. We have tested the compounds on the cell line such as MCF‐7; U87‐MG; SCC‐25; and HEK‐293T, via WST‐1 assay. Eight compounds showed IC50 values ranging 3.9–10 μM; against the cell line MCF‐7. The best compounds of all were KMS9 (IC50=3.83 μM), KMS5 (IC50=4.14 μM), and KBS8 (IC50=8.24 μM), which promoted apoptosis in MCF‐7 cells. KMS5 and KMS9 compounds showed G1 cell cycle arrest, while compound KBS8 showed G2 cell cycle arrest. Insilco ADME studies were carried out. Molecular docking and dynamics experiments showed how KMS5, KMS9, and KBS8 bind to the active region of the EGFR family – a group of receptor tyrosine kinase (RTK) proteins (PDB ID: 7JXP, 2.16 Å). Further structural modifications of the KMS5, KMS9, and KBS8 may improve their activity against breast cancer.

Acacia nilotica (L.) Delile as New Potential Inhibitors of 2019 Novel Coronavirus (Covid-19): Molecular Docking Study

The COVID-19 pandemic caused by SARS-CoV-2 has created an urgent need for effective therapeutics and vaccines. This study aimed to investigate the inhibitory activity of Acacia nilotica, a medicinal plant commonly used to treat various diseases in tropical and subtropical regions, against SARS-CoV-2 main proteases (Mpro) and spike proteins. Based on published literature, 22 compounds derived from Acacia nilotica were selected and assessed for their drug likeliness using Lipinski's rule of five and the SwissADME web tool. The compounds that fulfilled Lipinski's rule were subjected to molecular docking with Mpro (PDB ID: 6LU7) and spike proteins (PDB ID: 6LXT) using the Molecular Operating Environment software MOE. Among the 13 compounds docked with the main proteases and spike proteins of SARS-CoV-2, catechin-5-O-gallate, catechin-7-gallate, cetechin-3-O-gallate, cetechin-4-O-gallate, and gallocatechin-7-gallate was demonstrated superior inhibitory activity against Mpro and spike proteins compared to hydroxychloroquine, dexamethasone, and favipiravir. These findings indicate Acacia nilotica's potential as a source for developing specific therapeutic agents against SARS-CoV-2, pending further validation through wet lab experiments.

Exploring the antimicrobial and antioxidative potential of Leucas aspera (Willd.) Link: Phytochemical screening, molecular docking, and HR-LC/MS profiling against SARS-CoV-2 protein 3CLPro, Spike and RDB

BackgroundLeucas aspera (Willd.) Link, a member of the Lamiaceae family and commonly known as "Thumbai," is found throughout India and has been utilized in traditional Indian medicine to treat various ailments. PurposeThis study entails methanolic extraction of Leucas aspera (Willd.) Link using a Soxhlet apparatus, followed by phytochemical screening and antioxidant activity assessment. MethodsThe L. aspera methanolic leaf extract displayed a phenolic content of 100 µg/ml, consisting of 3.02 mg of gallic acid dry weight equivalents and a flavonoid content of 100 µg/ml with 3.35 mg quercetin equivalents per dry weight. The extract's free radical scavenging capabilities were at 150 µg/ml in DPPH, showing an 87% effectiveness compared to the standard ascorbic acid 49% inhibition capacity. The ABTS radical scavenging activity in 100 µg/ml extract measured 64.32%, phosphomolybdate assay indicated 86.89%, and hydroxide radical scavenging capacity showed 126.72%. Antibacterial activity was also assessed through agar well diffusion assays against Klebsiella pneumoniae, Salmonella typhi, Staphylococcus aureus, and Leucobacter sp., Where K. pneumoniae exhibits the highest zone of inhibition. The methanolic crude extract of L. aspera was further using TLC, FT-IR and HR-LC/MS to identify functional groups and phytocompound present in the extract. ResultsHRLC-MS was used to conduct metabolite profiling of the methanolic crude extract of L. aspera leaves, discovering 37 positive and 43 negative compounds. To evaluate the ADMET properties and predict the drug-likeness of these 80 phytochemicals, an in silico analysis was performed. The results of this analysis revealed that only 19 of the compounds met the ADMET limitations and had suitable Log P values. Molecular docking of the 19 compounds against the SARS-CoV-2 main protease (3CLPro) protein (PDB ID: 6LU7) and spike protein receptor binding domain (SGp-RBD) protein (PDB ID: 2GHV) revealed Famprofazone and Loxtidine compounds having the highest binding affinity with LibDock scores of 105.53 and 116.70 respectively. ConclusionThus, our findings could serve as potential active molecules of L. aspera against this target protein. This study provides further proof of bioactive compounds produced by the L. aspera leaf extract.

Synthesis, structural elucidation, ion flotation and biological evaluation of Ni(II) and Zn(II) Complexes featuring a heterocyclic thiosemicarbazide ligand with their computational studies

Herein, Ni(II) and Zn(II) complexes were synthesized using the heterocyclic thiosemicarbazide ligand (Z)-N-(2-oxoindolin-3-ylidene)nicotinohydrazide (H2L). The structures and geometries of these complexes were identified using elemental analysis, FT-IR, UV-Visible, Mass spectroscopy and thermogravimetric analysis (TGA). These techniques confirmed the composition of the target chelates as [Ni₂(HL)₂Cl₂(H₂O)₄].3H₂O with an octahedral geometry and [Zn(HL)(OAc)(H₂O)] with a tetrahedral geometry. Conductivity measurements indicated the non-ionic nature of the complexes. Moreover, the chelation patterns, structural configurations, and molecular interactions within the complexes were further corroborated through quantum mechanical computations, specifically density functional theory (DFT).An ion flotation method was employed to investigate the removal of nickel and zinc ions from aqueous solutions. This approach involved the formation of a complex between Ni(II) or Zn(II) ions and H₂L, followed by flotation using oleic acid (HOL) as the surfactant. Various parameters, including pH, surfactant and metal ion concentrations, the presence of foreign ions, and temperature, were systematically tested to determine the optimal flotation conditions. Furthermore, the compounds were evaluated for their effects on human carcinoma cells and their antibacterial properties. Additionally, molecular docking studies of the ligand, H₂L and its complexes were performed using the XP Glide module within the Schrödinger suite, targeting HepG2 (PDB ID: 2OH4) and MCF-7 (PDB ID: 3W2S) cell lines.

Visualizing Volumetric and Segmentation Data using Mol* Volumes & Segmentations 2.0.

Ever-increasing availability of experimental volumetric data (e.g., in.ccp4,.mrc,.map,.rec,.zarr,.ome.tif formats) and advances in segmentation software (e.g., Amira, Segger, IMOD) and formats (e.g.,.am,.seg,.mod, etc.) have led to a demand for efficient web-based visualization tools. Despite this, current solutions remain scarce, hindering data interpretation and dissemination. Previously, we introduced Mol* Volumes & Segmentations (Mol* VS), a web application for the visualization of volumetric, segmentation, and annotation data (e.g., semantically relevant information on biological entities corresponding to individual segmentations such as Gene Ontology terms or PDB IDs). However, this lacked important features such as the ability to edit annotations (e.g., assigning user-defined descriptions of a segment) and seamlessly share visualizations. Additionally, setting up Mol* VS required a substantial programming background. This article presents an updated version, Mol* VS 2.0, that addresses these limitations. As part of Mol* VS 2.0, we introduce the Annotation Editor, a user-friendly graphical interface for editing annotations, and the Volumes & Segmentations Toolkit (VSToolkit) for generating shareable files with visualization data. The outlined protocols illustrate the utilization of Mol* VS 2.0 for visualization of volumetric and segmentation data across various scales, showcasing the progress in the field of molecular complex visualization. © 2024 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: VSToolkit-setting up and visualizing a user-constructed Mol* VS 2.0 database entry Basic Protocol 2: VSToolkit-visualizing multiple time frames and volume channels Support Protocol 1: Example: Adding database entry idr-13457537 Alternate Protocol 1: Local-server-and-viewer-visualizing multiple time frames and volume channels Support Protocol 2: Addition of database entry custom-tubhiswt Basic Protocol 3: VSToolkit-visualizing a specific channel and time frame Basic Protocol 4: VSToolkit-visualizing geometric segmentation Basic Protocol 5: VSToolkit-visualizing lattice segmentations Alternate Protocol 2: "Local-server-and-viewer"-visualizing lattice segmentations Basic Protocol 6: "Local-server-and-viewer"-visualizing multiple volume channels Support Protocol 3: Deploying a server API Support Protocol 4: Hosting Mol* viewer with VS extension 2.0 Support Protocol 5: Example: Addition of database entry empiar-11756 Support Protocol 6: Example: Addition of database entry emd-1273 Support Protocol 7: Editing annotations Support Protocol 8: Addition of database entry idr-5025553.

Synthesis, single crystal investigations, DFT studies, biological activities, DNA cytotoxicity and molecular docking studies of copper(II) complex derived from the new o-vanillin Schiff base ligand

A novel Schiff base derivative, (E)-N’-(2-hydroxy-3-methoxybenzylidene)-2-phenylacetohydrazide (HMPH, H2L), and its Cu(II) complex were synthesized through the direct condensation of o-vanillin with phenylacetichydrazide in ethanol under reflux conditions. The synthesized ligand was identified usingelemental analysis, Fourier transform infrared (FTIR) and ultraviolet–visible (UV–Vis.) spectroscopy. The structures of HMPH (C16H16N2O3)2 and its Cu(II) complex [Cu(L)(H2O)]·H2O (C16H16N2CuO4·H2O) were analysed by single crystal X-ray diffraction technique. The X-ray diffraction results showed that HMPH crystallised in an orthorhombic Pca21 space group with a Z value of 8, while [Cu(L)(H2O)]·H2O crystallised in a monoclinic C 2/c space group with the same z value. The Cu(II) ion is coordinated to the acetohydrazide ligands via hydrazone nitrogen, aceto oxygen (N(2) and O(1)) and hydroxyl O(2) atoms. In addition to the single crystal structures of HMPH and [Cu(L)(H2O)]·H2O, the optimised molecular structures, molecular electrostatic potential meps, molecular orbital energy values, and interactions between DNA bases and molecular structures are determined by DFT/B3LYP/6-311G(d, p) for HMPH and DFT/B3LYP/LanL2DZ for [Cu(L)(H2O)]·H2O. The copper complex was found to be more potent than the organic ligand in terms of antimicrobial activity, with a strong anti-biofilm effect even at low MIC values. The cytotoxicity of the synthesized compounds was investigated on MDA-MB-231 cell lines. The [Cu(L)(H2O)]·H2O complex was found to be more lethal than the HMPH ligand. Furthermore, molecular docking studies of HMPH and [Cu(L)(H2O)]·H2O with P. aeruginosa ATCC27853 (PDB ID: 6P8U) were presented to explain the observed antibacterial activity and the mechanism-of-action.

Repurposing FDA-approved drugs for COVID-19: targeting the main protease through multi-phase in silico approach.

The COVID-19 pandemic has created an urgent need for effective therapeutic agents. The SARS-CoV-2 Main Protease (Mpro) plays a crucial role in viral replication and immune evasion, making it a key target for drug development. While several studies have explored Mpro inhibition, identifying FDA-approved drugs with potential efficacy remains a critical research focus. This study aims to identify FDA-approved drugs that could inhibit SARS-CoV-2 Mpro. Using computational screening, we seek compounds that share structural similarities with a known co-crystallized ligand (PRD_002214) and exhibit strong binding affinity to the enzyme, providing viable candidates for COVID-19 treatment. A systematic in silico approach was used, screening 3009 FDA-approved drugs. The initial screening focused on structural similarity to PRD_002214 (PDB ID: 6LU7), followed by molecular docking studies to predict binding affinity. Promising compounds were further analyzed through molecular dynamics (MD) simulations to evaluate their stability and interactions with Mpro over 100 ns. Of the 3009 FDA-approved drugs screened, 74 were selected for initial evaluation. After refinement, 28 compounds underwent docking analysis, with eight showing strong binding potential to Mpro. Molecular docking assessed the binding affinity and interaction of the selected compounds with Mpro. MD simulations were conducted on the top compound, Atazanavir, to study its dynamic interactions. MM-GBSA, PLIP, and PCAT analyses were used to validate binding affinity and interactions. Eight compounds, including Carfilzomib, Atazanavir, Darunavir, and others, exhibited promising binding affinities. Among them, Atazanavir showed the highest binding strength and was selected for further MD simulation studies. These simulations revealed that Atazanavir forms stable interactions with Mpro, demonstrating favorable binding and dynamic stability. The binding affinity was further confirmed through MM-GBSA, PLIP, and PCAT analyses, supporting Atazanavir's potential as an effective Mpro inhibitor. In silico results suggest that Atazanavir is a promising candidate for targeting SARS-CoV-2 Mpro, with strong binding affinity and dynamic stability. These findings support its potential as a lead compound for further preclinical and clinical testing, though in vitro and in vivo validation are needed to confirm its therapeutic efficacy against COVID-19.

Molecular Modelling of Resveratrol Derivatives with SIRT1 for the Stimulation of Deacetylase Activity.

Resveratrol is a polyphenol that is found in plants and has been proposed to have a potential therapeutic effect through the activation of SIRT1, which is a crucial member of the mammalian NAD+ -dependent deacetylases. However, how its activity is enhanced toward specific substrates by resveratrol derivatives has not been studied. This study aimed to evaluate the types of interaction of resveratrol and its derivatives with SIRT1 as the target protein, as well as to find out the best ligand with the strangest interaction with SIRT1. In this study, we employed the extensive molecular docking analysis using AutoDock Vina to comparatively evaluate the interactions of resveratrol derivatives (22 molecules from the ZINC database) as ligands with SIRT1 (PDB ID: 5BTR) as a receptor. The ChemDraw and Chem3D tools were used to prepare 3D structures of all ligands and energetically minimize them by the MM2 force field. The molecular docking and visualizations showed that conformational change in resveratrol derivatives significantly influenced the parameter for docking results. Several types of interactions, including conventional hydrogen bonds, carbon-hydrogen bonds, Pi-donor hydrogen bonds, and Pi-Alkyl, were found via docking analysis of resveratrol derivatives and SIRT1 receptors. The possible activation effect of resveratrol 4'-(6-galloylglucoside) with ZINC ID: ZINC230079516 with higher binding energy score (-46.8608 kJ/mol) to the catalytic domain (CD) of SIRT1 was achieved at the maximum value for SIRT1, as compared to resveratrol and its other derivatives. Finally, resveratrol 4'-(6-galloylglucoside), as a derivative for resveratrol, has stably interacted with the CD of SIRT1 and might be a potential effective activator for SIRT1.

Evaluations of FDA-approved Drugs Targeting 3CLP of SARS-CoV-2 Employing a Repurposing Strategy.

The SARS-CoV-2 coronavirus (COVID-19) has raised innumerable global concerns, and few effective treatment strategies have yet been permitted by the FDA to lighten the disease burden. SARS-CoV-2 3C-like proteinase (3CLP) is a crucial protease and plays a key role in the viral life cycle, as it controls replication, and thus, it is viewed as a target for drug design. In this study, we performed structure-based virtual screening of FDA drugs approved during 2015-2019 (a total of 220 drugs) for interaction with the active site of 3CLP (PDB ID 6LU7) using AutoDock 4.2. We report the top ten drugs that outperform the reported drugs against 3CLP (Elbasvir and Nelfinavir), particularly Cefiderocol, having the highest affinity among the compounds tested, with a binding energy of -9.97 kcal/mol. H-bond (LYS102:HZ2-ligand: O49), hydrophobic (ligand-VAL104), and electrostatic (LYS102:NZ-ligand: O50) interactions were observed in the cefiderocol-3CLP complex. The docked complex was subjected to a 50 ns molecular dynamics study to check its stability, and stable RMSD and RMSF graphs were observed. Accordingly, we suggest cefiderocol might be effective against SARS-CoV-2 and urge that experimental validation be performed to determine the antiviral efficacy of cefiderocol against SARS-CoV-2. Along with these, cefiderocol is effective for treating respiratory tract pathogens and a wide range of gram-negative bacteria for whom there are limited therapeutic alternatives. This article aimed to explore the FDA-approved drugs as a repurposing study against 3CLP for COVID-19 management.

Reactivity of three pyrimidine derivatives, potential analgesics, by the DFT method and study of their docking on cyclooxygenases-1 and 2

Three pyrimidine derivatives, namely 4-[4-(dimethylamino)phenyl]-6-(pyridin-4-yl)pyrimidin-2-amine (DMPN), 4-(4-aminophenyl)-6-[4-(dimethylamino)phenyl]pyrimidin-2-ol (DMPO) and 4-(4-aminophenyl)-6-[4-(dimethylamino)phenyl]pyrimidine-2-thiol (DMPS), with analgesic properties established by a QSAR study, were subjected to reactivity parameter studies using the DFT method, at the B3LYP/6-311++G(d,p) level of theory. Studies of the docking of these molecules to cyclooxygenases 1 (PDB ID: 5U6X) and 2 (PDB ID: 5F19) were also carried out using the CB-Dock online program. Reactivity parameter calculations revealed that the three derivatives are less stable to internal electron transfer, with the lowest energy gap ∆E ranging from 3.63 eV to 3.88 eV, compared with 6.03 eV for ibuprofen (IBP). These derivatives possess the lowest chemical hardnesses η from 1.81eV to 1.94eV versus 3.02eV for IBP and are better electrophiles than IBP with chemical electrophilicity index values ω from 3.20eV to 3.88eV versus 2.64eV for IBP. These derivatives possess greater chemical reactivity than ibuprofen. All three derivatives also feature electrophilic and nucleophilic attack sites. The docking results show that all three derivatives react with cyclooxygenases in the same areas of reactivity as most NSAIDs. These ligands are more active on COX-2 than COX-1, according to complex stability scores which are stronger with COX-2 than with COX-1. In addition, all three derivatives are more active on COX-2 than ibuprofen, with stability score values of -8.6 kcal/mol for DMPN, -9.2 kcal/mol for DMPO, -8.9 kcal/mol for DMPS and -7.6 kcal/mol for IBP. The DMPO ligand forms the most stable complex with COX-2. These three derivatives thus appear to be selective COX-2 inhibitors, with higher stability scores than ibuprofen. All three derivatives also have good absorption, distribution, metabolism and toxicity properties. They can therefore be used as drugs.

Discovery of novel pyrrolo[2,3-d]pyrimidine derivatives as anticancer agents: virtual screening and molecular dynamic studies

ABSTRACT CDK/Cyclins are dysregulated in several human cancers. Recent studies showed inhibition of CDK4/6 was responsible for controlling cell cycle progression and cancer cell growth. In the present study, atom-based and field-based 3D-QSAR, virtual screening, molecular docking and molecular dynamics studies were done for the development of novel pyrrolo[2,3-d]pyrimidine (P2P) derivatives as anticancer agents. The developed models showed good Q 2 and r 2 values for atom-based 3D-QSAR, which were equal to 0.7327 and 0.8939, whereas for field-based 3D-QSAR the values were 0.8552 and 0.6255, respectively. Molecular docking study showed good-binding interactions with amino acid residues such as VAL-101, HIE-100, ASP-104, ILE-19, LYS-147 and GLU-99, important for CDK4/6 inhibitory activity by using PDB ID: 5L2S. Pharmacophore hypothesis (HHHRR_1) was used in the screening of ZINC database. The top scored ZINC compound ZINC91325512 showed binding interactions with amino acid residues VAL-101, ILE-19, and LYS-147. Enumeration study revealed that the screened compound R1 showed binding interactions with VAL 101 and GLN 149 residues. Furthermore, the Molecular dynamic study showed compound R1, ZINC91325512 and ZINC04000264 having RMSD values of 1.649, 1.733 and 1.610 Å, respectively. These ZINC and enumerated compounds may be used for the development of novel pyrrolo[2,3-d]pyrimidine derivatives as anticancer agent.

Veratric Acid as a Potential Antidiabetic Agent: Molecular Docking and In vivo Enzyme Inhibition Studies with Insights from STz-NA Induced Diabetic Rat Model

Streptozotocin-nicotinamide (STz-NA) has proven to be an effective agent in inducing type 2 diabetes (T2DM) in experimental models due to its genotoxic impact on pancreatic β-cells. STz reduces nicotinamide adenine dinucleotide (NAD+) through the glucose transporter GLUT2, leading to cellular damage, DNA strand breaks, and cell death. Nicotinamide (NA), a biochemical precursor of NAD+ and poly-ADP-ribose-polymerase-1 (PARP-1) inhibitor, plays a crucial protective role by modulating NAD+ levels, which are essential in ATP production and other metabolic processes. Excessive DNA damage, however, triggers PARP-1 over-activation, depleting cellular reserves and resulting in cell necrosis. This study further investigates the antidiabetic and hepatoprotective effects of Veratric Acid (VA) by comparing it to Glibenclamide. Utilizing Computer-Aided Drug Design (CADD), VA was identified as a structurally similar compound with potential antidiabetic properties. Molecular docking studies targeting proteins, such as GLUT-1 (PDB ID: 4PYP) and 1BSI, along with in vivo assays in STz-NA-induced diabetic Wistar rats, were conducted. VA demonstrated significant binding affinity and molecular interactions comparable to standard antidiabetic agents, showing inhibitory effects on liver enzymes SGOT and SGPT, and supporting its potential role in diabetes management. Docking and histopathology results revealed that VA effectively reduced blood glucose, improved insulin levels, and enhanced liver function in diabetic rats. Additionally, VA promoted insulin secretion from pancreatic β-cells and upregulated insulin-related markers, with minimal hepatotoxicity compared to Glibenclamide. VA treatment significantly improved enzymatic and non-enzymatic antioxidant levels, lowered lipid peroxidation, and improved lipid profiles, which were confirmed by histopathological liver observations. Veratric Acid at low doses effectively modulates blood glucose and diabetes-related biochemical parameters, highlighting its promise as a safer, natural therapeutic alternative for diabetes treatment.