3D-QSAR studies on purine-carbonitriles as cruzain inhibitors: comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA)

Cruzain has been identified as the major cysteine protease of Trypanosoma cruzi, the etiological cause of Chaga's disease. For this reason, many efforts have been undertaken to design new inhibitors against this enzyme. Recently, molecules having a purine or triazine nucleus have been reported as potent non-peptidic inhibitors of cruzain. In order to gain an insight into the structural requirements that can lead to the improvement of the activity of these molecules, in this paper we report the CoMFA and CoMSIA studies of a series of purine-carbonitriles as cruzain inhibitors. Quantum semi-empirical calculations of the inhibitors inside the active site of cruzain were used as an approach to obtain reliable conformations for molecular alignment. Two different molecular alignments were used, resulting in 3 CoMFA models and 31 CoMSIA models. These models correspond to all of the possible combinations among five fields: steric, electrostatic, hydrophobic, hydrogen bond donor, and hydrogen bond acceptor. Highly predictive models were obtained. Based on the q(2) values, the best CoMFA model had an r(2) = 0.98 and a q(2) = 0.73, whereas the best CoMSIA model retrieved an r(2) = 0.88 and a q(2) = 0.62. All models were validated with a rigorous procedure using an external test set. Contour maps obtained from these models show a preference toward the purine ring and indicate that bulky groups with a negative potential at the 3- and 5-positions of the phenyl ring are important structural requirements for inhibitory activity against cruzain.