We developed a Monte-Carlo method based QSAR model to predict urease inhibiting potency of molecules using SMILES and GRAPH descriptors on an existing diverse database of urease inhibitors. The QSAR model satisfies all the statistical parameters required for acceptance as a good model. The model is applied to identify urease inhibitors among the wide range of compounds in the phytochemical database, NPACT, as a test case. We combine the ligand-based and structure-based drug discovery methods to improve the accuracy of the prediction. The method predicts pIC50 and estimates docking score of compounds in the database. The method may be applied to any other database or compounds designed in silico to discover novel drugs targeting urease. File list (6) download file view on ChemRxiv Manuscript_Smiles_2020Modified.pdf (2.46 MiB) download file view on ChemRxiv Fig.S1_Ligand_Interaction.pdf (818.05 KiB) download file view on ChemRxiv Fig.S2_Ligand_Inophyllum.pdf (379.61 KiB) download file view on ChemRxiv Data Sheet S1-UreaseInhDB436pic50.txt (31.44 KiB) download file view on ChemRxiv TableS1_FinallyAceeptedFAF.xls (46.00 KiB) download file view on ChemRxiv TableS2_qed_table.xls (38.50 KiB) Monte-Carlo method based QSAR model to discover phytochemical urease inhibitors using SMILES and GRAPH descriptors.
<div>COVID19 has compelled the scientific community to search for an effective drug that can
cure; a vaccine or an immunity booster that can prevent the disease. As of now, it is tough to
discover a new drug and vaccine discovery is even tougher. Drug repurposing is a shortcut to
drug discovery for COVID19. Even this has been proved unsatisfactory. Symptomatic
treatment and immunity boosters are only alternatives left. Holy Tulsi (Ocimum sanctum) has
been known as an ancient remedy for cure of common cold and respiratory ailment in India
vis-a-vis also has been prescribed as one of the recommended ingredients in the immunity
booster preparations. The ethanolic extract of aerial parts of Tulsi is reported to contain
flavonoids and polyphenolic acids, which are also reported earlier to have anti-viral
properties experimentally. Therefore, we undertake the in silico analysis of the
phytochemicals as inhibitors of main protease of SARS-CoV-2 virus. The result suggests that
the flavonoids and polyphenolic compounds of Tulsi, especially luteolin-7-O-glucuronide and
chlorogenic acid may covalently bind to the active residue Cys145 of main protease and
irreversibly inhibit the viral enzyme. Further experimental validations are required to
establish the theoretical findings. <br></div>
Epidermal growth factor receptor tyrosine kinase (EGFR-TK) is one of the key regulators that exhibit pivotal role in proliferation of cancer cell. Quinazolinones are studiedly widely as effective EGFR-TK inhibitor because of their higher affinity to bind with adenosine triphosphate (ATP) binding site of receptor tyrosine kinases. However, their toxicity due to non-specific binding to tyrosine kinase in non-cancerous normally dividing cells of the body limits its applicability as a cancer therapeutics. In the present investigation a series of thirty-four novel synthesized thiazolo- [2, 3-b] quinazolinones were studied in silico as EGFR-TK inhibitors. All the thirty-four compounds were screened against EGFR-TK domain using multiple software’s (AutoDock Vina, Argus Lab, YASARA, and MOE). The interactions of the ligands with amino acid residues, namely, Lys721, Met769 and Asp831 of the active site were through the functional groups on aryl substituents at position 3 and 5 of the thiazolo- [2, 3-b] quinazolinone scaffold. The methyl substituents at position 8 of the ligands had prominent hydrophobic interactions in the active site cavity of EGFR-TK domain. The compounds 5ab, 5aq, and 5bq were predicted to be non-toxic and drug-like by in silico ADMET investigations. These compounds were considered for further investigation due to their non-toxicity and higher docking score ranking in different docking methods. The molecular dynamics (MD) simulation for 100 ns of docked complexes revealed the stability of these compounds. The binding free energy determined using Molecular Mechanics Generalized Born Model and Solvent Accessibility (MM-GBSA) method indicate that thiazolo- [2, 3-b] quinazolinone has high inhibitory efficacy similar to the standard drug, erlotinib (5ab - 22.45, 5aq -22.23, 5bq -20.76, and erlotinib -24.11 kcal/mol). In silico studies and MD simulations indicated that compounds (5ab, 5aq and 5bq) could be potential EGFR-TK inhibitors and require further validation as cancer therapeutics using carcinoma cell lines.<br><p></p>
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