Structure-based drug design studies on a series of aldolase inhibitors

Journal of the Brazilian Chemical Society

Andricopulo, Adriano D.¹  Santos, Ricardo N. dos¹  Ferreira, Leonardo G.¹  Universidade de São Paulo, São Carlos, Brazil¹ 

关键词: African trypanosomiasis;    drug;    design;    inhibitors;    QSAR;    molecular modeling;   

DOI  :  10.5935/0103-5053.20130026

学科分类：化学（综合）

来源: SciELO

【 摘 要 】

Human African trypanosomiasis, also known as sleeping sickness, is a major cause of death in Africa, and for which there are no safe and effective treatments available. The enzyme aldolase from Trypanosoma brucei is an attractive, validated target for drug development. A series of alkyl-glycolamido and alkyl-monoglycolate derivatives was studied employing a combination of drug design approaches. Three-dimensional quantitative structure-activity relationships (3D QSAR) models were generated using the comparative molecular field analysis (CoMFA). Significant results were obtained for the best QSAR model (r2 = 0.95, non-cross-validated correlation coefficient, and q2 = 0.80, cross-validated correlation coefficient), indicating its predictive ability for untested compounds. The model was then used to predict values of the dependent variables (pKi) of an external test set, and the predicted values were in good agreement with the experimental results. The integration of 3D QSAR, molecular docking and molecular dynamics simulations provided further insight into the structural basis for selective inhibition of the target enzyme.

【 授权许可】

Unknown