QSAR based virtual screening derived identification of a novel hit as a SARS CoV-229E 3CLpro Inhibitor: GA-MLR QSAR modeling supported by molecular Docking, molecular dynamics simulation and MMGBSA calculation approaches

R D Jawarkar; Ravindrakumar L Bakal; Magdi E A Zaki; Sami Al-Hussain; Arabinda Ghosh; Ajaykumar Gandhi; Nobendu Mukerjee; Abdul Samad; Vijay H Masand; Israa Lewaa

doi:10.1016/j.arabjc.2021.103499

QSAR based virtual screening derived identification of a novel hit as a SARS CoV-229E 3CL^pro Inhibitor: GA-MLR QSAR modeling supported by molecular Docking, molecular dynamics simulation and MMGBSA calculation approaches

Arab J Chem. 2022 Jan;15(1):103499. doi: 10.1016/j.arabjc.2021.103499. Epub 2021 Oct 19.

Authors

Affiliations

¹ Department of Medicinal Chemistry, Dr. Rajendra Gode Institute of Pharmacy, University-Mardi Road, Amravati, Maharashtra, 444603, India.
² Department of Chemistry, Faculty of Science, Al-Imam Mohammad Ibn Saud Islamic university, Riyadh 13318, Saudi Arabia.
³ Microbiology Division, Department of Botany, Gauhati University, Guwahati, Assam 781014, India.
⁴ Department of Chemistry, Government College of Arts and Science, Aurangabad, Maharashtra 431 004, India.
⁵ Department of Microbiology; Ramakrishna Mission Vivekananda Centenary College, Akhil Mukherjee Rd, Chowdhary Para, Rahara, Khardaha, Kolkata, West Bengal 700118, India.
⁶ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tishk International University, Erbil, Kurdistan Region, Iraq.
⁷ Department of Chemistry, Vidyabharti Mahavidyalaya, Camp Road, Amravati Maharashtra, India.
⁸ Department of Business Administration, Faculty of Business Administration, Economics & Political Science, The British University in Egypt (BUE), Cairo, Egypt.

Abstract

Congruous coronavirus drug targets and analogous lead molecules must be identified as quickly as possible to produce antiviral therapeutics against human coronavirus (HCoV SARS 3CLpro) infections. In the present communication, we bear recognized a HIT candidate for HCoV SARS 3CLpro inhibition. Four Parametric GA-MLR primarily based QSAR model (R2:0.84, R2adj:0.82, Q2loo: 0.78) was once promoted using a dataset over 37 structurally diverse molecules along QSAR based virtual screening (QSAR-VS), molecular docking (MD) then molecular dynamic simulation (MDS) analysis and MMGBSA calculations. The QSAR-based virtual screening was utilized to find novel lead molecules from an in-house database of 100 molecules. The QSAR-vS successfully offered a hit molecule with an improved _PEC₅₀ value from 5.88 to 6.08. The benzene ring, phenyl ring, amide oxygen and nitrogen, and other important pharmacophoric sites are revealed via MD and MDS studies. Ile164, Pro188, Leu190, Thr25, His41, Asn46, Thr47, Ser49, Asn189, Gln191, Thr47, and Asn141 are among the key amino acid residues in the S1 and S2 pocket. A stable complex of a lead molecule with the HCoV SARS 3CLpro was discovered using MDS. MM-GBSA calculations resulted from MD simulation results well supported with the binding energies calculated from the docking results. The results of this study can be exploited to develop a novel antiviral target, such as an HCoV SARS 3CLpro Inhibitor.

Keywords: 3CLpro, 3C like Protease; FDA, Food and Drug Administration; GA-MLR; GA-MLR, Genetic Algorithm Multilinear Regression; HCoV SARS 3CLpro; HCoV-HKU1, Human coronavirus HKU1; HCoV-NL63, Human coronavirus NL63; HCoVs, human coronaviruses; Lead; MD, Molecular Docking; MDS, molecular dynamic simulation; MERS, Middle East Respiratory Syndrome; MMGBSA calculations; MMGBSA, Molecular Mechanics Generalized Born and Surface Area; Molecular docking and MD simulation; OECD, Organization for Economic Corporation and Development; QSAR based virtual screening; QSAR, Quantitative Structure Activity Relationship; RNA, Ribo-nucleic acid; SARS, severe acute respiratory sign; VS, Virtual Screening.