QSAR analysis was performed using 20 MT1 agonist and 18 MT2 agonist. MODI was 0.6373 in case of MT1 agonist and 0.6299 in case of MT2 agonist. QSAR model for MT1 receptor agonist was pKd = 16.24793(+/- 0.93539) +1.0924(+/-0.18831) ALogP -0.11399(+/-0.01383) apol +0.59876(+/-0.16599) C2SP3 -10.29435(+/-2.81413) E3p and for MT2 receptor agonist was pKd = 6.38692(+/-0.91098) +0.87139(+/-0.20258) ALogP -0.0351(+/-0.00542) AMR +3.33079 (+/-0.80377) SpMin6_Bhm +146.76208(+/-28.14492) VE2_Dt with statistical parameter as Q^2:0.79167, r^2 :0.88878, |r0^2-r'0^2|:0.04633,k:1.03159, [(r^2-r0^2)/r^2]:0.01013, k':0.96695, [(r^2- '0^2)/r^2]:0.06226 and Q^2:0.81401, r^2:0.97384, |r0^2-r'0^2|:0.1039, k:0.98543, [(r^2-r0^2)/r^2]:0.08048, k':1.01351, [(r^2-r'0^2)/r^2]:0.18717 respectively; comply with the Golbraikh and Tropsha acceptable model criteria. The results from MLR Y Randomization test in case of MT1 agonist was cRp^2: 0.7665 and MT2 agonist was cRp^2: 0.7284. Applicability domain were identified by Euclidean and Mahalanobis Distance Method. Finally it was clear that all the predicted data are inside the area of observed data points and also some data are purely overlapped.Dhaka Univ. J. Pharm. Sci. 15(1): 7-19, 2016 (June)
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.
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