Pyridones as NNRTIs against HIV-1 mutants: 3D-QSAR and protein informatics

Abstract

CoMFA and CoMSIA based 3D-QSAR of HIV-1 RT wild and mutant (K103, Y181C, and Y188L) inhibitory activities of 4-benzyl/benzoyl pyridin-2-ones followed by protein informatics of corresponding non-nucleoside inhibitors' binding pockets from pdbs 2BAN, 3MED, 1JKH, and 2YNF were analysed to discover consensus features of the compounds for broad-spectrum activity. The CoMFA/CoMSIA models indicated that compounds with groups which lend steric-cum-electropositive fields in the vicinity of C5, hydrophobic field in the vicinity of C3 of pyridone region and steric field in aryl region produce broad-spectrum anti-HIV-1 RT activity. Also, a linker rendering electronegative field between pyridone and aryl moieties is common requirement for the activities. The protein informatics showed considerable alteration in residues 181 and 188 characteristics on mutation. Also, mutants' isoelectric points shifted in acidic direction. The study offered fresh avenues for broad-spectrum anti-HIV-1 agents through designing new molecules seeded with groups satisfying common molecular fields and concerns of mutating residues.

Combined Pharmacophore Modeling, 3D-QSAR, Homology Modeling and Docking Studies on CYP11B1 Inhibitors

“…A series of models were constructed with an increasing number of partial least squares (PLS) analysis factors. The numbers of components in the PLS models were optimized by using the cross-validated correlation coefficient (Q 2 ), non-cross-validated correlation coefficient (R 2 ), standard error estimate (SEE) and F-statistic values (F ) , etc ., which were obtained from the leave-one-out (LOO) cross-validation procedures [37,38]. According these parameters, the best model was chosen to predict bioactivities of compounds.…”

Recent Advances in the Design and Development of Non‐nucleoside Reverse Transcriptase Inhibitor Scaffolds

“…According to the SAR and structure-based drug-design strategies, the substituents on C3, C4, and C6 of the 2-pyridone ring are important for the anti-HIV-1 activity. [32] By using these results and isostericp rinciple, pyridinone derivatives 54 and 55 were prepared, whichs howed sub-micromolar IC 50 values against HIV-1 RT (Figure 26). [22a] Rationalh ybridization and crystallographic overlay of two structurally distinct lead compounds TMC125 and R221239 led to compound 56 as ap otent anti-HIV-1 agent with an EC 50 value of 0.15 mm ( Figure 27).…”

Synthesis, Biological Evaluation, and Molecular Modeling Studies of Chiral Chloroquine Analogues as Antimalarial Agents

“…(vi) PLS analysis. The CoMFA and CoMSIA 3D-QSAR models were derived using the PLS regression procedure of SYBYL (39). The predictive ability of the model was measured in terms of leave-one-out predicted cross-validated r 2 (r cv 2 or Q 2 ), as shown in equation 2.…”

“…The number of components leading to the lowest standard error of prediction (SEP) was used as the optimum number of components (ONC) to generate the final PLS regression models. The models were validated through the bootstrapping analysis for 100 runs and the cross-validation analysis (leave-half-out and leave 20% out; 50 runs each) (39). The CoMFA and CoMSIA equations were plotted as contour maps to express the percent contribution of the respective fields to the activity.…”