Establishing the Role of Iridoids as Potential Kirsten Rat Sarcoma Viral Oncogene Homolog G12C Inhibitors Using Molecular Docking; Molecular Docking Simulation; Molecular Mechanics Poisson–Boltzmann Surface Area; Frontier Molecular Orbital Theory; Molecular Electrostatic Potential; and Absorption, Distribution, Metabolism, Excretion, and Toxicity Analysis

Author:

Alamri Mubarak A.1ORCID,Alawam Abdullah S.2,Alshahrani Mohammed Merae3ORCID,Kawsar Sarkar M. A.4ORCID,Prinsa 5,Saha Supriyo6ORCID

Affiliation:

1. Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia

2. Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh 11623, Saudi Arabia

3. Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Najran University, 1988, Najran 61441, Saudi Arabia

4. Laboratory of Carbohydrate and Nucleoside Chemistry, Department of Chemistry, Faculty of Science, University of Chittagong, Chittagong 4331, Bangladesh

5. Siddhartha Institute of Pharmacy, Near IT-Park, Sahastradhara Road, Dehradun 248001, Uttarakhand, India

6. Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Premnagar, Dehradun 248007, Uttarakhand, India

Abstract

The RAS gene family is one of the most frequently mutated oncogenes in human cancers. In KRAS, mutations of G12D and G12C are common. Here, 52 iridoids were selected and docked against 8AFB (KRAS G12C receptor) using Sotorasib as the standard. As per the docking interaction data, 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester (dock score: −9.9 kcal/mol), 6′-O-trans-para-coumaroyl geniposidic acid (dock score: −9.6 kcal/mol), 6-O-trans-cinnamoyl-secologanoside (dock score: −9.5 kcal/mol), Loganic acid 6′-O-beta-d-glucoside (dock score: −9.5 kcal/mol), 10-O-succinoylgeniposide (dock score: −9.4), Loganic acid (dock score: −9.4 kcal/mol), and Amphicoside (dock score: −9.2 kcal/mol) showed higher dock scores than standard Sotorasib (dock score: −9.1 kcal/mol). These common amino acid residues between iridoids and complexed ligands confirmed that all the iridoids perfectly docked within the receptor’s active site. The 100 ns MD simulation data showed that RMSD, RMSF, radius of gyration, and SASA values were within range, with greater numbers of hydrogen bond donors and acceptors. MM/PBSA analysis showed maximum binding energy values of −7309 kJ/mol for 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester. FMO analysis showed that 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester was the most likely chemically reactive molecule. MEP analysis data highlighted the possible electrophilic and nucleophilic attack regions of the best-docked iridoids. Of all the best-docked iridoids, Loganic acid passed Lipinski, Pfizer, and GSK filters with a similar toxicity profile to Sotorasib. Thus, if we consider these iridoids to be KRAS G12C inhibitors, they will be a boon to mankind.

Funder

Prince Sattam bin Abdulaziz University

Publisher

MDPI AG

Subject

Chemistry (miscellaneous),Analytical Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Molecular Medicine,Drug Discovery,Pharmaceutical Science

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