QSAR-based prediction of anti-HCV activity of thiourea derivatives

Quantitative structure–activity relationship (QSAR) studies were performed on a series of thioureas to explore the physico-chemical parameters responsible for their activity against the hepatitis C virus (HCV)-infected AVa5 cell. The physico-chemical parameters were calculated using WIN CAChe 6.1. Multiple linear regression analysis, after the variables selection by factor analysis, was performed to derive QSAR models which were further evaluated for their statistical significance and predictive power by internal and external validation. The developed QSAR model had the correlation coefficient (R) = 0.928 and cross-validated squared correlation coefficient (Q ²) = 0.751. The selected significant QSAR model indicates that hydrophobicity, dielectric energy, valence connectivity index (order 1), conformational minimum energy and highest occupied molecular orbital of the whole molecule play an important role in the anti-HCV activity of thioureas.     

2D- and 3D-QSAR modelling,molecular docking and in vitro evaluation studies on 18β-glycyrrhetinic acid derivatives against triple-negative breast cancer cell line

Abstract

Triple-negative breast cancers (TNBCs) are one of the most aggressive and complex forms of cancers in women. TNBCs are commonly known for their complex heterogeneity and poor prognosis. The present work aimed to develop a predictive 2D and 3D quantitative structure–activity relationship (QSAR) models against metastatic TNBC cell line. The 2D-QSAR was based on multiple linear regression analysis and validated by Leave-One-Out (LOO) and external test set prediction approach. QSAR model presented regression coefficient values for training set (r²), LOO-based internal regression (q²) and external test set regression (pred_r²) which are 0.84, 0.82 and 0.75, respectively. Five properties, Epsilon4 (electronegativity), ChiV3cluster (valence molecular connectivity index), chi3chain (retention index for three-membered ring), TNN5 (nitrogen atoms separated through 5 bond distance) and nitrogen counts, were identified as important structural features responsible for anticancer activity of MDA-MB-231 inhibitors. Five novel derivatives of glycyrrhetinic acid (GA) named GA-1, GA-2, GA-3, GA-4 and GA-5 were semi-synthesised and screened through the QSAR model. Further, in vitro activities of the derivatives were analysed against human TNBC cell line, MDA-MB-231. The result showed that GA-1 exhibits improved cytotoxic activity to that of parent compound (GA). Further, atomic property field (APF)-based 3D-QSAR and scoring recognise C-30 carboxylic group of GA-1 as major influential factor for its anticancer activity. The significance of C-30 carboxylic group in GA derivatives was also confirmed by molecular docking study against cancer target glyoxalase-I. Finally, the oral bioavailability and toxicity of GA-1 were assessed by computational ADMET studies.

Communicated by Ramaswamy H. Sarma