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. 2023 Jun 28;28(13):5050.
doi: 10.3390/molecules28135050.

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

Mubarak A Alamri  1 , Abdullah S Alawam  2 , Mohammed Merae Alshahrani  3 , Sarkar M A Kawsar  4 , Prinsa  5 , Supriyo Saha  6
Affiliations

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

Mubarak A Alamri et al. Molecules. .

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.

Keywords: ADMET; FMO; Iridoids; KRAS G12C; MD simulation; MEP; MM/PBSA; Sotorasib; molecular docking.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Molecular docking interaction data for 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester, 10-O-succinoylgeniposide, Loganic acid 6′-O-beta-d-glucoside, 6-O-trans-cinnamoyl-secologanoside, Loganic acid, 6′-O-trans-para-coumaroyl geniposidic acid, Amphicoside, and Sotorasib.
Figure 1
Figure 1
Molecular docking interaction data for 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester, 10-O-succinoylgeniposide, Loganic acid 6′-O-beta-d-glucoside, 6-O-trans-cinnamoyl-secologanoside, Loganic acid, 6′-O-trans-para-coumaroyl geniposidic acid, Amphicoside, and Sotorasib.
Figure 1
Figure 1
Molecular docking interaction data for 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester, 10-O-succinoylgeniposide, Loganic acid 6′-O-beta-d-glucoside, 6-O-trans-cinnamoyl-secologanoside, Loganic acid, 6′-O-trans-para-coumaroyl geniposidic acid, Amphicoside, and Sotorasib.
Figure 1
Figure 1
Molecular docking interaction data for 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester, 10-O-succinoylgeniposide, Loganic acid 6′-O-beta-d-glucoside, 6-O-trans-cinnamoyl-secologanoside, Loganic acid, 6′-O-trans-para-coumaroyl geniposidic acid, Amphicoside, and Sotorasib.
Figure 2
Figure 2
(a–l) MD simulation data for Iridoids and Sotorasib with 8AFB.
Figure 2
Figure 2
(a–l) MD simulation data for Iridoids and Sotorasib with 8AFB.
Figure 2
Figure 2
(a–l) MD simulation data for Iridoids and Sotorasib with 8AFB.
Figure 2
Figure 2
(a–l) MD simulation data for Iridoids and Sotorasib with 8AFB.
Figure 2
Figure 2
(a–l) MD simulation data for Iridoids and Sotorasib with 8AFB.
Figure 2
Figure 2
(a–l) MD simulation data for Iridoids and Sotorasib with 8AFB.
Figure 2
Figure 2
(a–l) MD simulation data for Iridoids and Sotorasib with 8AFB.
Figure 2
Figure 2
(a–l) MD simulation data for Iridoids and Sotorasib with 8AFB.
Figure 2
Figure 2
(a–l) MD simulation data for Iridoids and Sotorasib with 8AFB.
Figure 2
Figure 2
(a–l) MD simulation data for Iridoids and Sotorasib with 8AFB.
Figure 2
Figure 2
(a–l) MD simulation data for Iridoids and Sotorasib with 8AFB.
Figure 3
Figure 3
FMO analysis data for 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester, 10-O-succinoylgeniposide, Loganic acid 6′-O-beta-d-glucoside, 6-O-trans cinnamoyl-secologanoside, Loganic acid, 6′-O-trans-para-coumaroyl geniposidic acid, Amphicoside, and Sotorasib.
Figure 3
Figure 3
FMO analysis data for 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester, 10-O-succinoylgeniposide, Loganic acid 6′-O-beta-d-glucoside, 6-O-trans cinnamoyl-secologanoside, Loganic acid, 6′-O-trans-para-coumaroyl geniposidic acid, Amphicoside, and Sotorasib.
Figure 3
Figure 3
FMO analysis data for 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester, 10-O-succinoylgeniposide, Loganic acid 6′-O-beta-d-glucoside, 6-O-trans cinnamoyl-secologanoside, Loganic acid, 6′-O-trans-para-coumaroyl geniposidic acid, Amphicoside, and Sotorasib.
Figure 4
Figure 4
MEP analysis data for 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester, 10-O-succinoylgeniposide, Loganic acid 6′-O-beta-d-glucoside, 6-O-trans cinnamoyl-secologanoside, Loganic acid, 6′-O-trans-para-coumaroyl geniposidic acid, Amphicoside, and Sotorasib.
Figure 4
Figure 4
MEP analysis data for 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester, 10-O-succinoylgeniposide, Loganic acid 6′-O-beta-d-glucoside, 6-O-trans cinnamoyl-secologanoside, Loganic acid, 6′-O-trans-para-coumaroyl geniposidic acid, Amphicoside, and Sotorasib.
Figure 4
Figure 4
MEP analysis data for 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester, 10-O-succinoylgeniposide, Loganic acid 6′-O-beta-d-glucoside, 6-O-trans cinnamoyl-secologanoside, Loganic acid, 6′-O-trans-para-coumaroyl geniposidic acid, Amphicoside, and Sotorasib.
Figure 4
Figure 4
MEP analysis data for 6-O-trans-p-coumaroyl-8-O-acetylshanzhiside methyl ester, 10-O-succinoylgeniposide, Loganic acid 6′-O-beta-d-glucoside, 6-O-trans cinnamoyl-secologanoside, Loganic acid, 6′-O-trans-para-coumaroyl geniposidic acid, Amphicoside, and Sotorasib.
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