Molecular docking and dynamics studies on novel benzene sulfonamide substituted pyrazole-pyrazoline analogues as potent inhibitors of Plasmodium falciparum Histo aspartic protease.

Malaria is the major health issue in African, Asian and Mediterranean regions of the world. Due to the emerging resistance by the parasites and mosquitoes for the current medications and insecticides, respectively, the malaria free human world can be attained only by the novel design and development of new anti-malarial drugs. Hence, we attempted to carry out in silico screening of benzene sulfonamide substituted pyrazole-pyrazoline series against Histo aspartic protease. Our results reveal that the 65% of the data set with the free binding energy in the range of -11.58 to -11.21 kcal/mol, which is categorized as 'high scoring'. Ligands are docked with the catalytic residues Asp 215, Ser 75, Thr 33 and Ala 217, respectively. Molecular dynamic simulation study of free enzyme and the enzyme complex with 4-(5-(4-methoxyphenyl)-1'phenyl-3'-(p-tolyl)-3,4-1'H,2H-[3,4'-bipyrazol]-2-yl)benezenesulfonamide indicated structural stability. The trajectory analysis of complex reveals that the HAP-ligand complex is more stable than the free HAP. We are of the opinion that our results will be useful for designing potential anti-malarial compounds. AbbreviationsADTauto dock toolsBSPPbenzene sulfonamide substituted pyrazole-pyrazolineCQchloroquineHAPhisto aspartic proteaseKKelvinMDmolecular dockingMM/PBSAmolecular mechanics/Poisson Boltzmann surface areaNVTnormal volume and temperatureNPTnormal pressure and temperatureNsnanosecondsPDBprotein data bank.pdbprogram data base formatP. falciparumPlasmodium falciparumPspicosecondsPMsplasmepsinsP. vivaxPlasmodium vivaxRgradius of gyrationRMSDroot mean square deviationRMSFroot mean square fluctuationWHOWorld Health OrganizationCommunicated by Ramaswamy H. Sarma.