3D-QSAR studies of substituted 1-(3, 3-diphenylpropyl)-piperidinyl amides and ureas as CCR5 receptor antagonists.
3D-QSAR studies on the derivatives of 1-(3,3-diphenylpropyl)-piperidinyl amide and urea as CCR5 receptor antagonists were performed by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA) methods to rationalize the structural requirements responsible for the inhibitory activity of these compounds. The global minimum energy conformer of the template molecule, the most active and pharmacokinetically stable molecule of the series, was obtained by systematic search and used to build structures of the molecules in the dataset. The best predictions for the CCR5-receptor were obtained with the CoMFA standard model (q (2) = 0.787, r (2) = 0.962) and CoMSIA model combined steric, electrostatic and hydrophobic fields (q (2) = 0.809, r (2) = 0.951). The predictive ability of CoMFA and CoMSIA were determined using a test set of 12 compounds giving predictive correlation coefficients of 0.855 and 0.83, respectively, indicating good predictive power. Further, the robustness of the model was verified by bootstrapping analysis. The contour maps produced by the CoMFA and CoMSIA models were used to identify the structural features relevant to the biological activity in this series. Based on the CoMFA and CoMSIA analysis, we have identified some key features in the series that are responsible for CCR5 antagonistic activity which may be used to design more potent 1-(3,3-diphenylpropyl)-piperidinyl derivatives and predict their activity prior to synthesis.
Aher
Yogesh D
YD
Centre of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, S. A. S. Nagar, Mohali, 160 062, India.
Agrawal
Avantika
A
Bharatam
Prasad V
PV
Garg
Prabha
P
D065100:CCR5 Receptor Antagonists; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008956:Models, Chemical; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D055672:Static Electricity; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
D065100:CCR5 Receptor Antagonists; D010880:Piperidines; D014508:Urea