Chemometric Modeling, Docking & In Silico Design of Pf Dhodh Inhibitors as Antimalarials

Abstract

Malaria is a global disease responsible for fever, headache and some time in severe cases extends to coma and death . Malaria is the one amongst the top ten more deadly forms of the disease (pneumonia, diarrohea, HIV AIDS, tuberculosis, measles, hepatitis B and malaria) and it acquires 85% part of global burden of all infectious disease burden. falcifarum malaria is the more deadly form amongst all types of malaria with acquiring 45% of total a malaria cases. Rapid resistance is a biggest problem towards all types of anti malarial drugs. So there is a significant unmet medical need for new, effective, and safe drugs. Inhibitors of PfDHODH have proven efficacy for the treatment of malaria. 3D QSAR studies on some 5-(2-methylbenzimidazol-1-yl)-N-alkylthiophene-2-carboxamide derivatives as PfDHODH inhibitors 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 alignment strategy was used for these compounds by means of Distill function defined in SYBYL x 1.2. The best CoMFA and CoMSIA models obtained for the training set were statistically significant with cross-validated coefficients (q2) of 0.669 and 0.727 and conventional coefficients (r2) of 0.971 and 0.966, respectively. Both the models were validated by an external test set of five compounds giving satisfactory prediction (r2 pred) of 0.799 and 0.815 for CoMFA and CoMSIA models, respectively. Further the robustness of the model was verified by bootstrapping analysis. Such model can also subjected to the HQSAR, TOPOMER CoMFA study and such can also give the satisfactory result and good correlation was achieved between the all of these modules. Generated CoMFA and CoMSIA models, Atomic contribution map along with docking study provides the useful information for the design of novel inhibitors with better PfDHODH inhibitory activity Based on such study the Novel compounds are designed and subjected to Docking as well as In Silico ADMET study and finally the best compound is decided rationally. Keywords 3D QSAR; Malaria; PfDHODH inhibitors; CoMFA; CoMSIA; HQSAR; Docking; 5-(2-methylbenzimidazol-1-yl)-N-alkylthiophene-2-carboxamides