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Forty-one derivatives of spirooxindoles, active against HCT-116 colon cancer cells, underwent pharmacophore-based 3D-QSAR analysis to understand their correlation with anti-cancer activity. The study identified a seven-point pharmacophore model (ADHHRRR1) and QSAR models, offering insights for lead optimization and novel analogue design, thus advancing anti-cancer drug discovery. This research underscores the value of molecular modeling in elucidating structure-activity relationships and enhancing drug development efforts.

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The chemical composition of Ganoderma lucidum ethanol extracts was systematically analyzed and identified by ultra-high performance liquid chromatography-quadrupole electrostatic field orbitrap high-resolution mass spectrometry(UPLC-Orbitrap-HRMS). The fragmentation pattern of the representative chemical compounds was summarized, and the potential anti-liver fibrosis active compounds of G. lucidum acting on the farnesoid X receptor(FXR) target were studied to elucidate its pharmacodynamic substance basis. Preliminarily, 95 chemical constituents of G. lucidum ethanol extracts were identified, including 24 ganoderic acids, 9 ganoderenic acids, 13 lucidenic acids, 3 ganolucidic acids, 1 ganoderma lactone, 40 other triterpenoids, 4 fatty acids, and 1 other constituent. In addition, the fragmentation patterns of the representative compounds were also analyzed. The structural characteristics of ganoderic acids and ganoderenic acids were the C30 skeleton, containing free-COOH and-OH groups, which could easily lose H_2O and CO_2 to form fragment ions. The D-ring was mostly a five-membered ring, which was prone to breakage. Lucidenic acids were the lanosterolane-type of the C27 skeleton, and the side-chain structure became shorter and contained the same free-COOH and-OH compared with ganoderic acids, which had been reduced from 8 to 5 cartons and prone to lose H_2O and CO_2. Then, six reported FXR receptor agonists were selected to form a training set for establishing a pharmacophore model based on FXR ligands. The 95 identified chemical constituents of G. lucidum were matched with the pharmacophore, and the optimal pharmacophore model 02(sensitivity=0.750 00, specificity=0.555 56, ROC=0.750) was selected for the virtual screening of the G. lucidum compound library through the validation of the test set. Finally, 31 potential G. lucidum active constituents were screened and chosen to activate the FXRs. The ADMET results showed that ganoderic acid H and lucidenic acid J had less than 90% plasma protein binding rate and no hepatotoxicity, which could be used as FXR activators for developing clinical drugs for the treatment of liver fibrosis, either alone or in combination.

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Non-alcoholic fatty liver disease (NAFLD) is a growing global health concern due to its potential to progress into severe liver diseases. Targeting the bile acid receptor FXR has emerged as a promising strategy for managing NAFLD. Building upon our previous research on FXR partial agonism, the present study investigates a series of 1,3,4-trisubstituted-pyrazol amide derivatives as FXR antagonists, aiming to delineate the structural features for antagonism. By means of 2D-QSAR (quantitative structure-activity relationships) modelling techniques, we elucidated the key structural elements responsible for the antagonistic properties of these derivatives. We then employed QPhAR, an open-access software, to identify key molecular features within the compounds that enhance their antagonistic activity. Additionally, 3D-QSAR modelling allowed us to analyse the steric and electrostatic fields of aligned 3D structures, further refining our understanding of structure-activity relationships. Subsequent molecular dynamics simulations provided insights into the binding mode interactions between the compounds and FXR, with varying potencies, confirming and complementing the findings from 2D-QSAR, pharmacophore, and 3D-QSAR modelling. Particularly, our study highlighted the significance of hydrophobic interactions in conferring potent antagonism by the 1,3,4-trisubstituted-pyrazol amide derivatives against FXR. Overall, this work underscores the potential of 1,3,4-trisubstituted-pyrazol amides as FXR antagonists for NAFLD treatment. Notably, our reliance on open-access software fosters reproducibility and broadens the accessibility of our findings.

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Global public health is confronted with significant challenges due to the prevalence of cancer and the emergence of treatment resistance. This work focuses on the identification of cyclin-dependent kinase 2 (CDK2) through a systematic computational approach to discover novel cancer therapeutics. A ligand-based pharmacophore model was initially developed using a training set of seven potent CDK2 inhibitors. The obtained most robust model was characterized by three features: one donor (|Don|) and two acceptors (|Acc|). Screening this model against the ZINC database resulted in identifying 108 hits, which underwent further molecular docking studies. The docking results indicated binding affinity, with energy values ranging from -6.59 kcal mol⁻¹ to -7.40 kcal mol⁻¹ compared to the standard Roscovitine. The top 10 compounds (Z1-Z10) selected from the docking data were further screened for ADMET profiling, ensuring their compliance with pharmacokinetic and toxicological criteria. The top 3 compounds (Z1-Z3) chosen from the docking were subjected to Density Functional Theory (DFT) studies. They revealed significant variations in electronic properties, providing insights into the reactivity, stability, and polarity of these compounds. Molecular dynamics simulations confirmed the stability of the ligand-protein complexes, with acceptable RMSD and RMSF values. Specifically, compound Z1 demonstrated stability, around 2.4 Å, and maintained throughout the 100 ns simulation period with minimal conformational changes, stable RMSD, and consistent protein-ligand interactions.

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The translocator protein 18 kDa (TSPO) is an evolutionarily conserved mitochondrial transmembrane protein implicated in various neuropathologies and inflammatory conditions, making it a longstanding diagnostic and therapeutic target of interest. Despite the development of various classes of TSPO ligand chemotypes, and the elucidation of bacterial and non-human mammalian experimental structures, many unknowns exist surrounding its differential structural and functional features in health and disease. There are several limitations associated with currently used computational methodologies for modelling the native structure and ligand-binding behaviour of this enigmatic protein. In this perspective, we provide a critical analysis of the developments in the uses of these methods, outlining their uses, inherent limitations, and continuing challenges. We offer suggestions of unexplored opportunities that exist in the use of computational methodologies which offer promise for enhancing our understanding of the TSPO.

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Gamma-aminobutyric acid (GABA) signaling is the principal inhibitory pathway in the central nervous system. It is critical in neuronal cell proliferation and fate determination. Any aberration in GABA inhibition results in psychiatric and neurological diseases. Thus, modulating GABAergic neurotransmission has become the basis of drug therapy for psychiatric and several neurological diseases. Though GABA and muscimol are classical inhibitors of GABA receptors, the search for novel inhibitors continues unabated. In this study, the binding mechanism of GABA and muscimol was elucidated and applied in the search for small molecule GABAergic inhibitors using comprehensive computational techniques. It was revealed that a high-affinity binding of GABA and muscimol was mediated by a water molecule involving α1Thr129 and then stabilized by strong interactions including salt bridges with ß2Glu155 and α1Arg66 amidst hydrogen bonds, π-π stacking, and π -cation interactions with other residues. The binding of GABA and muscimol was also characterized by stability and deeper penetration into the hydrophobic core of the protein which resulted in conformational changes of the binding pocket and domain, by inducing correlated motions of the residues. Thermodynamics analysis showed GABA and muscimol exhibited total binding free energies of -19.85 ± 8.83 Kcal/mol and -26.55 ± 3.42 Kcal/mol, respectively. A pharmacophore model search, based on the energy contributions of implicating binding residues, resulted in the identification of ZINC68604167, ZINC19735138, ZINC04202466, ZINC00901626, and ZINC01532854 as potential GABA-mimetic compounds from metabolites and natural products libraries. This study has elucidated the binding mechanisms of GABA and muscimol and successfully applied in the identification of GABA-mimetic compounds.Communicated by Ramaswamy H. Sarma.

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Atherosclerosis is potentially correlated with several cardiac disorders that are greatly associated with cellular oxidative stress generation, inflammation, endothelial cells dysfunction, and many cardiovascular complications. Berberine is a natural isoquinoline alkaloid compound that widely modulates pathogenesis of atherosclerosis through its different curative potentials. This in silico screening study was designed to confirm the potent restorative properties of berberine chloride as a multitarget-mediated alkaloid against the CVDs and their complications through screening, identifying, visualizing, and evaluating its binding models, affinities, and interactions toward several CVDs-related targets as direct and/or indirect-mediated signals via inhibiting cellular ER stress and apoptotic signals and activating autophagy pathway. The drug-likeness properties of berberine were predicted using the computational QSAR/ADMET and Lipinski's RO5 analyses as well as in silico molecular docking simulations. The potent berberine-binding modes, residues-interaction patterns, and free energies of binding scores towards several CVDs-related targets were estimated using molecular docking tools. Furthermore, the pharmacokinetic properties and toxicological features of berberine were clearly determined. According to this in silico virtual screening study, berberine chloride could restore cardiac function and improve pathogenic features of atherosclerotic CVDs through alleviating ER stress and apoptotic signals, activating autophagy, improving insulin sensitivity, decreasing hyperglycemia and dyslipidemia, increasing intracellular RCT signaling, attenuating oxidative stress and vascular inflammation, and upregulating cellular antioxidant defenses in many cardiovascular tissues. In this in silico study, berberine chloride greatly modulated several potent CVDs-related targets, including SIGMAR1, GRP78, CASP3, BECN1, PIK3C3, SQSTM1/p62, LC3B, GLUT3, INSR, LDLR, LXRα, PPARγ, IL1ß, IFNγ, iNOS, COX-2, MCP-1, IL10, GPx1, and SOD3.

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The integration of computational resources and chemoinformatics has revolutionized translational health research. It has offered a powerful set of tools for accelerating drug discovery. This chapter overviews the computational resources and chemoinformatics methods used in translational health research. The resources and methods can be used to analyze large datasets, identify potential drug candidates, predict drug-target interactions, and optimize treatment regimens. These resources have the potential to transform the drug discovery process and foster personalized medicine research. We discuss insights into their various applications in translational health and emphasize the need for addressing challenges, promoting collaboration, and advancing the field to fully realize the potential of these tools in transforming healthcare.

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Alzheimer's disease (AD) is a progressive neurological disorder responsible for the cognitive dysfunction and cognitive impairment in the patients. Acetylcholinesterase inhibitors (AChEIs) are used to treat AD however, these only provided symptomatic relief and more efficient drug molecules are desired for the effective treatment of the disease. In this article, ligand-based drug-designing strategy was used to develop and validate a field-based 3D-QSAR pharmacophore model on quinazoline-based AChEIs reported in the literature. The validated pharmacophore model (AAAHR_1) was used as a prefilter to screen an ASINEX database via virtual screening workflow (VSW). The hits generated were subjected to MM-GBSA to identify potential AChEIs and top three scoring molecules (BAS 05264565, LEG 12727144 and SYN 22339886) were evaluated for thermodynamic stability at the target site using molecular dynamic simulations. Additionally, DFT study was performed to predict the reactivity of lead molecules towards acetylcholinesterase (AChE). Thus, by utilising various computational tools, three molecules were identified as potent AChEIs that can be developed as potential drug candidates for the treatment of AD.Communicated by Ramaswamy H. Sarma.

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VEGFR2 and FAK signaling pathways are interconnected and have synergistic effects on tumor angiogenesis, growth, and metastasis. Thus, instead of the conventional targeting of each of these proteins individually with a specific inhibitor, the present work aimed to discover novel dual inhibitors targeting both VEGFR2 and FAK exploiting their association. To this end, receptor-based pharmacophore modeling technique was opted to generate 3D pharmacophore models for VEGFR2 and FAK type II kinase inhibitors. The generated pharmacophore models were validated by assessing their ability to discriminate between active and decoy compounds in a pre-compiled test set of VEGFR2 and FAK active compounds and decoys. ZINCPharmer web tool was then used to screen the ZINC database purchasable subset using the validated pharmacophore models retrieving 42,616 hits for VEGFR2 and 28,475 hits for FAK. Subsequently, they were filtered using various filters leaving 13,023 and 6,832 survived compounds for VEGFR2 and FAK, respectively, with 124 common compounds. Based on molecular docking simulations, thirteen compounds were found to satisfy all necessary interactions with VEGFR2 and FAK kinase domains. Thus, they are predicted to have a possible dual VEGFR2/FAK inhibitory activity. Finally, SwissADME web tool showed that compound ZINC09875266 is not only promising in terms of binding pattern to our target kinases, but also in terms of pharmacokinetic properties.

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Targeting Heat shock protein 90 (HSP90) C-terminus is an important strategy to develop HSP90 inhibitors without inducing heat shock response. The development of C-terminal inhibitors, however, is hampered by a lack of understanding regarding the interaction between the HSP90 C-terminus and the present inhibitors. We collected seven classical and structurally diverse HSP90 C-terminal inhibitors and constructed a ligand-based pharmacophore model. The subsequent virtual screening and structural optimisation led to the identification of 2-heteroarylthio-N-arylacetamides as novel HSP90 C-terminal inhibitors. 9 and 27 exhibited strong antitumour activity in vitro by inhibiting proliferation and inducing apoptosis in multiple cancer cell lines. These compounds disrupted the interaction between HSP90 C-terminus and peptidylprolyl isomerase D, exerting a stronger inhibitory effect than novobiocin. 27 significantly induced the degradation of HSP90 clients without triggering heat shock response. In an in vivo study using 4T1 mice breast cancer models, 9 showed a potent antitumour effect without obvious toxicity.

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Colorectal cancer (CRC) is one of the most common cancers worldwide. Nowadays, owing to the complex mechanism of tumorigenesis, simultaneous inhibition of multiple targets is an important anticancer strategy. Recent studies have demonstrated receptor tyrosine kinase AXL (AXL) and histone deacetylase 2 (HDAC2) are closely associated with colorectal cancer. Herein, we identified five hit compounds concurrently targeting AXL and HDAC2 using virtual screening. Inhibitory experiments revealed these hit compounds potently inhibited AXL and HDAC2 in the nanomolar range. Among them, Hit-3 showed the strongest inhibitory effects which were better than that of the positive control groups. Additionally, MD assays showed that Hit-3 could bind stably to the AXL and HDAC2 active pockets. Further MTT assays demonstrated that Hit-3 showed potent anti-proliferative activity. Most importantly, Hit-3 exhibited significant in vivo antitumor efficacy in xenograft models. Collectively, this study is the first discovery of dual-targeting AXL/HDAC2 inhibitors for colorectal cancer treatment.

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Cancer is enlisted among the deadliest disease all over the world. The cyclin-dependent kinases 12 and 13 have been identified as cell cycle regulators. They conduct transcription and co-transcriptional processes by phosphorylating the C-terminal of RNA polymerase-II. Inhibition of CDK12 and 13 selectively presents a novel strategy to treat triple-negative breast cancer, but dual inhibitors are still lacking. Here, we report the screening of the natural product compound class against the dual CDK12/13 enzyme by employing various in silico methods. Complexes of CDK12 enzymes are used to form common feature pharmacophore models, whereas we perform receptor-based pharmacophore modelling on CDK13 enzyme owing to the availability of a single PDB. On conducting screening over the representative pharmacophores, the common drug-like screened natural products were shortlisted for conducting molecular docking studies. After molecular docking calculations, the candidates that showed crucial interaction with CDK12 and CDK13 enzymes were shortlisted for simulation studies. Five common docked candidates were selected for molecular dynamics simulations and free energy calculations. Based on the cut-off criteria of free energy calculations, one common hit was selected as the dual CDK12/13 inhibitor. The outcome concluded that the hit with ID CNP0386383 possesses drug-like properties, displays crucial interaction in the binding pocket, and shows stable dynamic behaviour and higher binding energy than the experimentally reported inhibitor of both CDK12 and CDK13 enzymes.Communicated by Ramaswamy H. Sarma.

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GPCRs are a family of transmembrane receptors that are profoundly linked to various neurological disorders, among which is Parkinson's disease (PD). PD is the second most ubiquitous neurological disorder after Alzheimer's disease, characterized by the depletion of dopamine in the central nervous system due to the impairment of dopaminergic neurons, leading to involuntary movements or dyskinesia. The current standard of care for PD is Levodopa, a dopamine precursor, yet the chronic use of this agent can exacerbate motor symptoms. Recent studies have investigated the effects of combining A2AR antagonist and 5-HT1A agonist on dyskinesia and motor complications in animal models of PD. It has been proved that the drug combination has significantly improved involuntary movements while maintaining motor activity, highlighting as a result new lines of therapy for PD treatments, through the regulation of both receptors. Using a combination of ligand-based pharmacophore modelling, virtual screening, and molecular dynamics simulation, this study intends on identifying potential dual-target compounds from IBScreen. Results showed that the selected models displayed good enrichment metrics with a near perfect receiver operator characteristic (ROC) and Area under the accumulation curve (AUAC) values, signifying that the models are both specific and sensitive. Molecular docking and ADMET analysis revealed that STOCK2N-00171 could be potentially active against A2AR and 5-HT1A. Post-MD analysis confirmed that the ligand exhibits a stable behavior throughout the simulation while maintaining crucial interactions. These results imply that STOCK2N-00171 can serve as a blueprint for the design of novel and effective dual-acting ligands targeting A2AR and 5-HT1A.Communicated by Ramaswamy H. Sarma.

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The sperm-specific channel CatSper (cation channel of sperm) controls the intracellular Ca2+ concentration ([Ca2+]i) and plays an essential role in sperm function. It is mainly activated by the steroid progesterone (P4) but is also promiscuously activated by a wide range of synthetic and physiological compounds. These compounds include diverse steroids whose action on the channel is so far still controversial. To investigate the effect of these compounds on CatSper and sperm function, we developed a high-throughput screening (HTS) assay to measure changes in [Ca2+]i in human sperm and screened 1,280 approved and off-patent drugs including 90 steroids from the Prestwick chemical library. More than half of the steroids tested (53%) induced an increase in [Ca2+]i and reduced the P4-induced Ca2+ influx in human sperm in a dose-dependent manner. Ten of the most potent steroids (activating and P4-inhibiting) were selected for a detailed analysis of their action on CatSper and their ability to act on sperm acrosome reaction (AR) and penetration in viscous media. We found that these steroids show an inhibitory effect on P4 but not on prostaglandin E1-induced CatSper activation, suggesting that they compete for the same binding site as P4. Pregnenolone, dydrogesterone, epiandrosterone, nandrolone, and dehydroepiandrosterone acetate (DHEA) were found to activate CatSper at physiologically relevant concentrations within the nanomolar range. Like P4, most tested steroids did not significantly affect the AR while stanozolol and estropipate slightly increased sperm penetration into viscous medium. Furthermore, using a hybrid approach integrating pharmacophore analysis and statistical modelling, we were able to screen in silico for steroids that can activate the channel and define the physicochemical and structural properties required for a steroid to exhibit agonist activity against CatSper. Overall, our results indicate that not only physiological but also synthetic steroids can modulate the activity of CatSper with varying potency and if bound to CatSper prior to P4, could impair the timely CatSper activation necessary for proper fertilization to occur.

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Bilophila wadsworthia is one of the prominent sources of hydrogen sulfide (H2S) production in appendices, excessive levels of which can result in a weaker colonic mucus barrier, inflammatory bowel disease, and colorectal cancer. Isethionate sulfite-lyase (IslA) enzyme catalyzes H2S production by cleaving CS bond in isethionate, producing acetaldehyde and sulfite. In this study, we aimed to identify potential substrate antagonists for IsIA using a structure-based drug design. Initially, pharmacophore-based computational screening of the ZINC20 database yielded 66 hits that were subjected to molecular docking targeting the isethionate binding site of IsIA. Based on striking docking scores, nine compounds showed strong interaction with critical IsIA residues (Arg189, Gln193, Glu470, Cys468, and Arg678), drug-like features, appropriate adsorption, metabolism, excretion, and excretion profile with non-toxicity. Molecular dynamics simulations uncovered the significant impact of binding the compounds on protein conformational dynamics. Finally, binding free energies revealed substantial binding affinity (ranging from -35.23 to -53.88 kcal/mol) of compounds (ZINC913876497, ZINC913856647, ZINC914263733, ZINC914137795, ZINC915757996, ZINC914357083, ZINC913934833, ZINC9143362047, and ZINC913854740) for IsIA. The compounds proposed herein through a multi-faceted computational strategy can be experimentally validated as potential substrate antagonists of B. wadsworthia's IsIA for developing new medications to curb gut-associated illness in the future.

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In search of new anti-breast cancer agents, the present study envisaged the design and synthesis of a series of benzopyran-chalcones. All the synthesized compounds were assayed for their in-vitro anticancer activity against ER + MCF-7 and triple-negative MDA-MB-231 breast cancer cell lines using SRB assay. The synthesized compounds were found active against ER + MCF-7 cell lines. Based on the in-vitro data, in-silico analysis was performed using hormone-dependent breast cancer targets such as hER-α and aromatase because the compounds showed activity against MCF-7 cells and none was active against MDA-MB-231. The in-silico results supported the in-vitro anticancer activity suggesting the affinity of compounds toward hormone-dependant breast cancer. Compounds 4A1 to 4A3 were found to be most cytotoxic to MCF-7 cells with IC50 values of 31.87, 22.95, and 20.34 µg/ml, respectively (Doxorubicin IC50: <10 µg/ml). In addition, they showed the interactions with the amino acid residues of a binding cavity of an hER-α. Furthermore, quantitative structure-activity relationship (QSAR) studies were performed to reveal the vital structural features required for anticancer activity against breast cancer. Molecular dynamic simulation studies of hER-α and 4A3 in comparison with the raloxifene complex ensure the appropriate refinement of compounds in the dynamic system. Additionally, a generated pharmacophore model explored the essential pharmacophoric features of the synthesized scaffolds with respect to clinically used drug molecules for optimal hormone-dependant anti-breast cancer activity.Communicated by Ramaswamy H. Sarma.

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Hepatocellular carcinoma (HCC) is a tumour pathology that lacks specific treatment and is predominantly resistant to chemotherapy. The inhibitory activity of Morinda citrifolia, an evergreen tree commonly called Noni, against various carcinomas especially HCC is widely acclaimed. This study was to assess the phytochemical constituents of the plant for inhibitory activity against B-Raf kinase (3C4C) in order to design drugs for HCC treatment. Molecular docking, pharmacophore modelling, induced-fit docking, molecular dynamics (MD) simulations and ADMET predictions were the computational techniques employed in this study to detect potential inhibitors of B-Raf kinase from 135 compounds of Morinda citrifolia. Soranjidiol, Thiamine, Lucidin, 2-Methyl-1,3,5-Trihydroxyanthraquinone and Rubiadin were the five top-scoring compounds ranging from -8.39 to -8.22 kcal/mol, however, the standard ligand, PLX4720, scored -11.26 kcal/mol. The five compounds, like PLX4720 demonstrated hydrogen bond interactions with active site amino acid residues such as GLN 530, CYS 532 and ASP 594. The main energy contributor to the interactions between the compounds and B-Raf kinase were pi-stacking, hydrogen bond, van der Waals and covalent energy. Better docking scores obtained in the induced-fit docking further validates the inhibitory potential of the Soranjidiol against the flexible protein. In MD simulations, Soranjidiol revealed good stability in the active site of the protein since significant conformational changes were not evident. These five compounds, unlike the standard compound, demonstrated adequate druglike properties and good safety profiles. Therefore, further studies should be undertaken so as to develop them into drugs against HCC.Communicated by Ramaswamy H. Sarma.

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A mini survey was employed in the search of herbs and spices which people believe could prevent them from contracting COVID-19. Phytochemicals which have been earlier implicated for the bioactivity of the afore-mentioned herbs and spices were identified through literature search. The phytochemicals were then subjected to pharmacore modelling, molecular docking and molecular dynamics simulation in order to identify phytochemicals that could serve as inhibitors of 3-Chymotryprin-like protease and RNA dependent-RNA polymerase of SARS-CoV-2. The drug-likeness and toxicity profile of the phytochemicals were afterwards predicted via ADMET studies. The mini survey showed ginger, garlic, bitter cola, as the lead-herbs which could find application in anti- COVID-19 therapy. Literature search revealed 27 phytochemicals were implicated for bioactivity of these herbs. Of these 27 phytoconstituents that were docked with 3-chymotrypsin-like protease and RNA dependent-RNA polymerase, the constituents of bitter cola had lower docking scores than other phytochemicals. MD simulation results showed that Garcinia biflavonoid I displayed less comformational changes and the better binding free energy. Also, the garcinia biflavonoids had relatively safe ADMET predictions. Hence, Garcinia biflavonoids and some other constituents of bitter cola could be further modified so as to obtain safe pharmaceutical intervention for the COVID-19 challenge.Communicated by Ramaswamy H. Sarma.

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Epidermal growth factor receptor (EGFR), being one of the most crucial receptor in cancer therapy, has been selected as a potential target for the present study. Ligand-based pharmacophore model (n = 30, R2=0.93 with root mean square deviation = 1.14, ΔCost = 144.27 and configuration cost = 21) was developed and validated with Fischer's randomisation (at 95% confidence), test set (n = 225, R2 pred = 0.81), external data set (n = 13, R2 pred = 0.95) and decoy set (n = 70), further the model has been used to search for novel EGFR inhibitors. The validated model was used for virtual screening of zinc database. A pool of 115,948 candidate molecules was screened through the model. Subsequently, molecules having predicted IC50<0.2 µM were selected for screening through drug-like properties filter. Based on pharmacokinetic profile (ADMET study), Lipinski's rule of five and Veber's rule, 62 molecules were shortlisted for molecular docking. Using consensus docking, five hit molecules were selected, which were further considered for molecular dynamics simulation. Additionally MM-GBSA analysis was carried which showed that affinity of hits towards the receptor of three compound mainly ZINC305, ZINC131796 and ZINC131785 were similar to the standard vanedtinib. The simulation, performed for 100 ns, revealed that two hit molecules, namely ZINC305 and ZINC131785, showing potential interactions at the ligand-binding domain of EGFR protein with good ligand-protein stability. Communicated by Ramaswamy H. Sarma.

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