3D-QSAR and molecular docking studies of 2-pyrimidinecarbonitrile derivatives as inhibitors against falcipain-3.
The three dimensional-quantitative structure activity relationship (3D-QSAR) studies were performed on a series of falcipain-3 inhibitors using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. A training set containing 42 molecules served to establish the QSAR models. The optimum CoMFA and CoMSIA models obtained for the training set were statistically significant with cross-validated correlation coefficients r(cv)(2) (q(2)) of 0.549 and 0.608, and conventional correlation coefficients (r(2)) of 0.976 and 0.932, respectively. An independent test set of 12 molecules validated the external predictive power of both models with predicted correlation coefficients (r(pred)(2)) for CoMFA and CoMSIA as 0.697 and 0.509, respectively. The docking of inhibitors into falcipain-3 active site using GOLD software revealed the vital interactions and binding conformation of the inhibitors. The CoMFA and CoMSIA field contour maps agree well with the structural characteristics of the binding pocket of falcipain-3 active site, which suggests that the information rendered by 3D-QSAR models and the docking interactions can provide guidelines for the development of improved falcipain-3 inhibitors.
School of Chemistry, University of Hyderabad, Hyderabad, India.
Angamba Meetei
AM
Potshangbam
Karunakar
K
Tanneeru
Bandi Madhusudhan
BM
Reddy
Lalitha
L
Guruprasad
D020134:Catalytic Domain; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D009570:Nitriles / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
D004791:Enzyme Inhibitors; D009570:Nitriles; D011743:Pyrimidines; D003546:Cysteine Endopeptidases; C443101:falcipain 3