Molecular Dynamics, Inhibitive, Structural Activity, and Toxicity Studies of Novel 4-aminoquinoline Imidazole Analogues Against Chloroquine-Resistant-Plasmodium falciparum (3D7 strain)

Abstract

Abstract Chloroquine resistance in Plasmodium falciparum, is the deadliest form of malaria. It is associated with several mutations of PfCRT (P. falciparum chloroquine resistant transporter): PfCRT is a protein group that serves as a transporter in the parasite's digesting vacuole membrane. In the quest to battle chloroquine-resistant—P. falciparum strains, this study aim to predict the anti-plasmodial activity of ten (10) novel 4-aminoquinoline imidazole (4AQI) analogues (new-sets), whose activity was modeled using a multi-linear regression algorithm; trained by the structural-activity data from fifteen (15) 4-aminoquinoline (4aq). Additionally, the study aim to understand the effect of electron delocalization and the extent to which the structural affinity of the new-sets has to the Pf3D7 protein. Results reveal that R2 value (0.9180), R2pred value (0.8276), and Q2 value (0.6672) obtained from the QSAR studies proofed to be sufficient for constructing and testing the QSAR model. According to molecular docking studies, it was understood that new-sets with electron withdrawing groups, such as, -CO2H, -NO2, -OH, F, Cl, and Br have a higher tendency toward plasmodium affinity than those with electron donating groups like -OCH3 and -NH2 against the Pf3D7 protein. All ten (10) 4AQI (new-sets) were approved as prospective drugs by the ADMET predictive study. Molecular dynamics results simulation at 50ns of time reveals that of all the new-sets, n16 and n21 stabilized the Pf3D7 (~ 0.1–0.2 Å) the most and better than chloroquine with respect to the protein structure. Furthermore, n16, n21, and chloroquine could provide flexibility in two amino acid regions 180–230 (~ 0.95–1.55Å) and 260–289 (~ 0.7–1.2Å). Additionally, n16 and n21 complexes showed retained a stable range of 210–250 number of hydrogen bonds, while chloroquine maintained a range of 180–220 hydrogen bonds.