Revealing the potency of 1,3,5-trisubstituted pyrazoline as antimalaria through combination of in silico studies

Abstract

The potency of 1,3,5-trisubstituted pyrazoline as an antimalarial agent has been studied through quantitative structure-activity relationship, molecular docking, and molecular dynamics simulation as a combination of in silico studies. The study commenced by applying quantitative structure-activity relationship (QSAR) to 25 derivative compounds using 3D-descriptor. The genetic algorithm and multiple linear regression analysis were used to construct the QSAR model, which resulting an equation that has Rtraining as 0.8100 and Rtest set as 0.9222. Descriptors involved in the QSAR equation are TDB4 m, TDB8s, RDF30e, and RDF552, all of which belong to the group of 3D autocorrelation and RDF. This result is in line with the principal component analysis, which shows that both group descriptors represent whole 3D descriptors. Molecular docking analysis is conducted to study the interaction between pyrazoline derivatives and the falcipain-2 enzyme. Interactions between compound 14 and falcipain-2 is describing by hydrogen bond against Glu14 amino acid residue, more pi-stacking interaction, and van der Waals. Chloroquine as a positive control also presented one hydrogen bond with Gly83, pi-sulfur against Cys42, and van der Waals. The stability of the ligand– enzyme interaction is evaluated by molecular dynamics simulation, and after 100 ns simulations, the root mean square deviation results show that compound 14 and chloroquine have a stable interaction with the falcipain-2 enzyme. Overall, this research provides the insight of 1,3,5-trisubstitued pyrazoline compounds as antimalaria by giving a QSAR equation and used to design a better falcipain-2 inhibitors.