Triple layered QSAR Studies on Substituted 1,2,4-Trioxanes as potential antimalarial agents

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The present study describes a successful application of combination of three different computational approaches to identify essential structural requirements in 3D chemical space for the modulation of the antimalarial activity of substituted 1,2,4-trioxanes. Each approach has its own advantages and disadvantages. The CoMFA and CoMSIA have been applied successfully to rationalize the 3D space in diverse substituted 1,2,4-trioxanes in terms of their steric, electrostatic, and hydrophobic interaction for their antimalarial activity. The developed models showed good statistical significance in internal validation (q2, group cross-validation and bootstrapping) and performed very well in predicting antimalarial activity of 43 substituted 1,2,4-trioxanes in the test set. The CoMFA, CoMSIA models not only provided the information about the favorable regions as reported in DS based pharmacophore but also give the information about the unfavorable regions in defining the potency. In addition the superiority of QuantitativePBA over GMCBA has been established. Further, the HQSAR studies based on the same training set also provided the 2D sub-structural requirements and showed good statistical significance in internal validation (r2cv, r2ncv) as well as predicted very well the antimalarial activity of the test set compounds. Thus, the three layered QSAR studies viz. Pharmacophore, CoMFA, CoMSIA and HQSAR may be useful for designing new substituted 1,2, 4-trioxane with potent antimalarial activity.

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