In silico-Based Structural Prediction, Molecular Docking and ADMET Analysis of Novel Imidazo-Quinoline Derivatives as Pf Purine Nucleoside Phosphorylase Inhibitors

Abstract

Introduction: The prolonged antimalarial therapy with the marketed drug has developed multi-resistant strains of Plasmodium parasites that emerge as a consequential global problem. Therefore, designing new antimalarial agents is an exclusive solution to overcome the alarming situation. Methods: The integrated computational perspectives, such as pharmacophore mapping, 3D-QSAR and docking studies have been applied to improve the activity of the imidazo-quinoline scaffold. The best hypothesis AARRR_1 (Survival score 5.4609) obtained through pharmacophore mapping revealed that imidazo-quinoline scaffold is found to be vital for antimalarial activity. The significant CoMFA (q2 = 0.728, r2 = 0.909) and CoMSIA (q2 = 0.633, r2 = 0.729) models, developed by using molecular field analysis with the PLS method, showed good predictive ability with r2 pred values of 0.9127 and 0.7726, respectively. Docking studies were performed using Schrodinger and GOLD software with the Plasmodium falciparum purine nucleoside phosphorylase enzyme (PDB ID-5ZNC) and results indicated that the imidazo-quinoline moiety facilitates the interaction with Tyr 160. Results: In addition, some compounds are screened from the ZINC database based on structural requirements to verify the relevance of the research. Finally, designed molecules and ZINC database compounds were screened through the ADMET tool to evaluate pharmacokinetic and druglikeness parameters. Conclusion: Thus, these exhaustive studies suggested that established models have good predictability and would help in the optimization of newly designed molecules that may lead to potent antimalarial activity for getting rid of resistance issues.