Classical and 3D-QSAR studies of cytochrome 17 inhibitor imidazole-substituted biphenyls

Abstract

Classical and 3D-quantitative structure–activity relationship (3D-QSAR) studies have been performed for a series of imidazole-substituted biphenyl derivatives (n = 28) having 17α-hydroxylase/17-20-lyase (CYP17) inhibitory activity. 3D-QSAR analyses were performed using molecular shape analysis (MSA), receptor surface analysis (RSA) and molecular field analysis (MFA). The chemometric tools used for the analysis are genetic function approximation (classical QSAR and MSA) and genetic partial least squares (MFA and RSA). The developed QSAR models suggest that the presence of an imidazole group at the para position of the biphenyl ring is favourable for the inhibitory activity. The MSA-derived model indicates the importance of different shadow parameters (Lx, Syz) as well as molecular rigidity. The MFA model suggests the interaction points near the phenyl ring and the imidazole ring, while the RSA model indicates the nature of the hypothetical receptor surface around the ring systems. The RSA-derived model was found to be the best model based on the highest internal (Q ² = 0.932) predictive power as well as criteria (0.858). According to external prediction statistics ( = 0.876), the MFA-derived model outperforms other models. Overall, there should be small (–H, –OH, –NH₂) hydrophilic hydrogen bond donor groups at the terminal phenyl ring (meta or para position) for optimum inhibitory activity.

Keywords:

• QSAR
• LFER
• MSA
• MFA
• RSA

Acknowledgement

One of the authors (PPR) thanks the University Grants Commission (UGC), New Delhi for a fellowship.