Machine learning-based drug design for identification of thymidylate kinase inhibitors as a potential anti-Mycobacterium tuberculosis

Journal of Biomolecular Structure and Dynamics, Год журнала: 2023, Номер 42(8), С. 3874 - 3886

Опубликована: Май 26, 2023

The rise of antibiotic-resistant Mycobacterium tuberculosis (Mtb) has reduced the availability medications for therapy, resulting in increased morbidity and mortality globally. Tuberculosis spreads from lungs to other parts body, including brain spine. Developing a single drug can take several decades, making discovery costly time-consuming. Machine learning algorithms like support vector machines (SVM), k-nearest neighbor (k-NN), random forest (RF) Gaussian naive base (GNB) are fast effective commonly used discovery. These ideal virtual screening large compound libraries classify molecules as active or inactive. For training models, dataset 307 was downloaded BindingDB. Among compounds, 85 compounds were labeled active, having an IC50 below 58 mM, while 222 inactive against thymidylate kinase, with 87.2% accuracy. developed models subjected external ZINC 136,564 compounds. Furthermore, we performed 100-ns dynamic simulation post trajectories analysis good interaction score molecular docking. As compared standard reference compound, top three hits revealed greater stability compactness. In conclusion, our predicted inhibit kinase overexpression combat tuberculosis.Communicated by Ramaswamy H. Sarma

Язык: Английский

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Novel series of hydrazones carrying pyrazole and triazole moiety: Synthesis, structural elucidation, quantum computational studies and antiviral activity against SARS-Cov-2

Journal of Molecular Structure, Год журнала: 2024, Номер 1317, С. 139016 - 139016

Опубликована: Дек. 1, 2024

Язык: Английский

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Assessing the efficacy of cinnamon compounds against H. pylori through molecular docking, MD Simulations and ADMET analyses

PLoS ONE, Год журнала: 2024, Номер 19(3), С. e0299378 - e0299378

Опубликована: Март 11, 2024

Antibiotics are the drugs that used for management of microbial diseases. However, these conventional synthetic can harmfully affect human health. Since phytochemicals extracted from natural sources and, hence relatively safer health, they enticing alternatives in this regard. Cinnamon is also one those plants which being employed as herbal medication centuries against certain infections due its significant therapeutic effectiveness. A well-known pathogenic bacterium called H . pylori causes a wide range illnesses body. This pathogen’s pathogenicity determined by virulent proteins. In study, some such proteins, included virB4 , virB8 and virB9 were selected to evaluate efficiency cinnamon compounds. These proteins identified different isolates The structural modelling all performed initially order proceed them molecular docking analysis. While, studies illustrated compounds, cinnamyl acetate showed binding interactions with benzyl benzoate another compound, docked well Afterwards, MD simulations incorporated explore interaction motions stability complexes. regard, resultant maps Bfactor, eigenvalues elastic network model, among other factors ensured stabilities respective After crucial estimations, underwent ADMET investigation assess their pharmacokinetic characteristics. SwissADME ADMETLab 2.0 server investigation. compiled findings servers revealed both, exhibited level drug-likeness conformity.

Язык: Английский

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Computer‐assisted Methods and Tools for Structure‐ and Ligand‐based Drug Design

Опубликована: Ноя. 29, 2024

Due to the increasing pandemic with current emerging and ongoing pathogenesis, situation overcome is getting difficult for humans. The research community keenly interested in computational approach therapeutics development, as we have seen pandemic, i.e., COVID-19. Although silico -based experiment not new community, advancement this going day by betterment of humankind. available earlier conventional strategies been successful developing novel drugs therapeutics; however, they a major drawback time cost. Interestingly, computer-assisted approaches are considerable interest due their efficacy accelerating drug development terms cost-effectiveness. Different potential molecules designed through approaches. Computer-assisted discovery significantly impacts overall process advanced high accuracy levels. Innovative techniques allow researchers integrate screen bulk high-throughput biological data generated globally repurposing or finding indications existing drugs. Therefore, study aims briefly introduce how structure- ligand-based were employed discovery. tools databases used perform these also described. Additionally, chapter discusses that using

Язык: Английский

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Involvement of the Opioidergic Mechanism in the Analgesic Potential of a Novel Indazolone Derivative: Efficacy in the Management of Pain, Neuropathy, and Inflammation Using In Vivo and In Silico Approaches

ACS Omega, Год журнала: 2023, Номер 8(25), С. 22809 - 22819

Опубликована: Июнь 12, 2023

Indazolones possess interesting pharmacological activities. The search for indazole and indazolone-containing nuclei as drugs is an important research area of medicinal chemistry. current work aims to evaluate a novel indazolone derivative against in vivo silico targets pain, neuropathy, inflammation. An (ID) was synthesized characterized using advanced spectroscopic techniques. Well-established animal models abdominal constriction, hot plate, tail immersion, carrageenan paw edema, Brewer's yeast-induced pyrexia were employed evaluating the potential ID at different doses (20-60 mg kg-1). Nonselective GABA antagonists, opioid antagonist naloxone (NLX) pentylenetetrazole (PTZ), assess role GABAergic opioidergic processes. antineuropathic drug evaluated vincristine-induced neuropathic pain model. In studies performed any possible interactions with target sites like cyclooxygenases (COX-I/II), GABAA, receptors. This study revealed that selected (doses 20-60 kg-1) efficiently hampered chemically thermally induced nociceptive responses, producing significant anti-inflammatory antipyretic effects. These effects produced by dose-dependent (i.e., kg-1 p range 0.001-0.01) comparison standards (p < 0.001). Antagonistic NLX (1.0 PTZ (15.0 involvement mechanism rather than mechanism. showed promising anti-static allodynia well. preferential binding According results investigation, may serve future therapeutic agent treatment pyrexia, chemotherapy-induced inflammatory pain.

Язык: Английский

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Identification of Phytochemicals from Arabian Peninsula Medicinal Plants as Strong Binders to SARS-CoV-2 Proteases (3CLPro and PLPro) by Molecular Docking and Dynamic Simulation Studies

Molecules, Год журнала: 2024, Номер 29(5), С. 998 - 998

Опубликована: Фев. 25, 2024

We provide promising computational (in silico) data on phytochemicals (compounds 1–10) from Arabian Peninsula medicinal plants as strong binders, targeting 3-chymotrypsin-like protease (3CLPro) and papain-like proteases (PLPro) of SARS-CoV-2. Compounds 1–10 followed the Lipinski rules five (RO5) ADMET analysis, exhibiting drug-like characters. Non-covalent (reversible) docking compounds demonstrated their binding with catalytic dyad (CYS145 HIS41) 3CLPro triad (CYS111, HIS272, ASP286) PLPro. Moreover, implementation covalent (irreversible) protocol revealed that only 7, 8, 9 possess warheads, which allowed formation bond (CYS145) in (CYS111) Root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius gyration (Rg) analysis molecular dynamic (MD) simulations complexation between ligands 9) PLPro was stable, there less ligands. Overall, silico inherent properties above unravel fact they can act reversible inhibitors for also showed novel to inhibit dual targets by irreversible inhibition, indicating effectiveness possibly developing future drugs against Nonetheless, confirm theoretical findings here, warrants investigations using suitable vitro vivo tests.

Язык: Английский

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Identification of and Mechanistic Insights into SARS-CoV-2 Main Protease Non-Covalent Inhibitors: An In-Silico Study

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(4), С. 4237 - 4237

Опубликована: Фев. 20, 2023

The indispensable role of the SARS-CoV-2 main protease (Mpro) in viral replication cycle and its dissimilarity to human proteases make Mpro a promising drug target. In order identify non-covalent inhibitors, we performed comprehensive study using combined computational strategy. We first screened ZINC purchasable compound database pharmacophore model generated from reference crystal structure complexed with inhibitor ML188. hit compounds were then filtered by molecular docking predicted parameters drug-likeness pharmacokinetics. final dynamics (MD) simulations identified three effective candidate inhibitors (ECIs) capable maintaining binding within substrate-binding cavity Mpro. further comparative analyses complexes terms dynamics, thermodynamics, free energy (BFE), interaction energies modes. results reveal that, when compared inter-molecular electrostatic forces/interactions, van der Waals (vdW) forces/interactions are far more important association determining high affinity. Given un-favorable effects interactions-association destabilization competitive hydrogen bond (HB) interactions reduced affinity arising un-compensable increase desolvation penalty-we suggest that enhancing vdW while avoiding introducing deeply buried HBs may be strategy future optimization.

Язык: Английский

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In-silico studies to recognize repurposing therapeutics toward arginase-I inhibitors as a potential onco-immunomodulators

Frontiers in Pharmacology, Год журнала: 2023, Номер 14

Опубликована: Апрель 18, 2023

Rudolf Virchow was the first person to point out important link between immune function and cancer. He did this by noticing that leukocytes were often found in tumors. Overexpression of arginase 1 (ARG1) inducible nitric oxide synthase (iNOS) myeloid-derived suppressor cells (MDSCs) tumour-associated macrophages (TAMs) depletes both intracellular extracellular arginine. TCR signalling is slowed as a result, same types produce reactive oxygen nitrogen species (ROS RNS), which aggravates situation. Human I double-stranded manganese metalloenzyme helps L-arginine break down into L-ornithine urea. Thus, quantitative structure-activity relationship (QSAR) analysis performed unearth unrecognised structural aspects crucial for arginase-I inhibition. In work, balanced QSAR model with good prediction performance clear mechanistic interpretation developed using dataset 149 molecules encompassing broad range scaffolds compositions. The made meet OECD standards, all its validation parameters have values are higher than minimum requirements (R2tr = 0.89, Q2LMO 0.86, R2ex 0.85). present study linked factors inhibitory action, including proximity lipophilic atoms molecule's centre mass (within 3A), position donor ring (exactly 3 bonds away), surface area ratio. As OAT-1746 two others only inhibitors development at time, we QSAR-based virtual screening 1650 FDA compounds taken from zinc database. screening, 112 potential hit PIC50 value less 10 nm against receptor. created model's application domain evaluated relation most active identified utilising training set molecules. shown Williams plot, top molecule, ZINC000252286875, has low leverage HAT i/i h* 0.140, placing it towards boundary usable range. Furthermore, one docking score -10.891 kcal/mol (PIC50 10.023 M) isolated molecular docking. Protonated ZINC000252286875-linked arginase-1 showed 2.9 RMSD, whereas non-protonated had 1.8. RMSD plots illustrate protein stability protonated ZINC000252286875-bound states. Protonated-ZINC000252286875-bound proteins contain 25 Rg. protein-ligand combination exhibits 25.2-Rg, indicating compactness. ZINC000252286875 stabilised targets binding cavities posthumously. Significant root mean square fluctuations (RMSF) seen small number residues time 500 ns unprotonated ligands interacted throughout simulation. bound Lys64, Asp124, Ala171, Arg222, Asp232, Gly250. Aspartic acid residue 232 exhibited 200% ionic contact. 500-ns simulations-maintained ions. Salt bridges aided six Lys68, Asp117, His126, Lys224, Asp232 residues. Lys224 interactions. deprotonated states, GbindvdW, GbindLipo, GbindCoulomb energies played role. Moreover, meets ADMET standards serve drug. current analyses successful locating novel potent molecule inhibits effectively nanomolar concentrations. results investigation can be used develop brand-new an alternative immune-modulating cancer therapy.

Язык: Английский

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Phytochemicals-based β-amyloid cleaving enzyme-1 and MAO-B inhibitors for the treatment of Alzheimer’s disease: molecular simulations-based predictions

Journal of Biomolecular Structure and Dynamics, Год журнала: 2023, Номер unknown, С. 1 - 13

Опубликована: Окт. 10, 2023

Alzheimer's disease (AD) is among the highly prevalent neurodegenerative disorder of aging brain and allied with cognitive behavioral abnormalities. Unfortunately, there very limited drug discovery for effective management AD, clinically approved drugs have efficacy. Consequently, an immediate demand development new compounds that ability to act as multitarget-directed ligands (MTDLs). As major pathological targets disease, current study aimed investigate lead natural bioactive including apigenin, epigallocatechin-3-gallate, berberine, curcumin, genistein, luteolin, quercetin, resveratrol their inhibitory potentials against β-amyloid cleaving enzyme-1 (BACE1) monoamine oxidase-B (MAO-B) enzymes. The were docked target enzymes (MAO-B BACE1) using MOE software subsequent molecular dynamics simulations (MDS) studies. docking analysis revealed these phytochemicals (MTDLs) showed good interactions compared reference inhibitors. Among eight phytocompounds, epigallocatechin-3-gallate compound was active inhibitor both targets, highest scores residues Furthermore, result one in complex (epigallocatechin-3-gallate/BACE1, epigallocatechin-3-gallate/MAO-B, reference/BACE1 reference/MAO-B) further validated by MDS. According findings our study, has potential be a candidate use treatment neurological illnesses like AD. This MTDL may exploited create disease-modifying features.Communicated Ramaswamy H. Sarma.

Язык: Английский

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In silico exploration of the potential inhibitory activities of in-house and ZINC database lead compounds against alpha-glucosidase using structure-based virtual screening and molecular dynamics simulation approach

Journal of Biomolecular Structure and Dynamics, Год журнала: 2024, Номер unknown, С. 1 - 11

Опубликована: Янв. 31, 2024

Inhibitors of α-glucosidase have been used to treat type-2 diabetes (T2DM) by preventing the breakdown carbohydrates into glucose and prevent enhancing conversion. Structure-based virtual screening (SBVS) was generate novel chemical scaffold-ligand inhibitors. The databases were screened against receptor using SBVS molecular dynamics simulation (MDS) techniques in this study. Based on docking studies, three two compounds inhibitors chosen from a commercial database (ZINC) an In-house for study respectively. mode binding interactions selected later predicted their inhibitory potential. Finally, one out lead compound ZINC shortlisted based interactions. Furthermore, MDS post-MDS strategies refine validate leads along with reference acarbose/α-glucosidase. Hits' ability inhibit SBVS, indicating that these good activities. inhibitor's structure may serve as templates design inhibitors, vitro testing confirm anti-diabetic potential is necessary. These insights can help rationally new effective drugs.

Язык: Английский

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