Identification of New Candidate Inhibitors Able to Prevent Erythrocyte Invasion in Malaria by Drug Screening

In Nowadays malaria still remains the parasitic disease causing the highest number of deaths, accounting for 619,000 fatalities. The Plasmodium parasites that cause malaria have separate life cycles in both humans and female Anopheles mosquitoes, existing in various forms throughout this process. The main reason for observing the disease is that merozoites sustain their existence by invading erythrocytes. Existing drugs affect the parasite's ability to digest hemoglobin. Drug resistance is also involved in this process. In this study, have been focused to develop new drug candidate molecules for evade drug resistance. To evade drug resistance, the aim was to prevent merozoites from invading erythrocytes.

The invasion of merozoites into erythrocytes consists of several stages: Attachment, deformation, apical junction formation, and tight junction formation. For this purpose, the docking calculations have been done between the invasion proteins such as MSP1, pvDBP, phRH5, AMA1 and candidates. The candidates obtained from the malaria box set were subjected to conformational scanning and geometry optimization in the Spartan'14 program to determine their physicochemical properties. According to the obtained results from the AutoDock Vina and multiple regression analyses were conducted for each protein to examine the relationship between binding affinities and the calculated physicochemical parameters of the candidates.

In the regression study of 200 molecules examined for 4 different proteins, 108 molecules were included for DBP, 96 for MSP1, 90 for AMA1 and 96 for RH5, and 21 common molecules were observed for all proteins.

Twenty-one molecules showed correlation with the proteins studied. Among these molecules, MMV019074, MMV019662 and MMV665881 were suggested as candidate drug leads in terms of their binding affinities, physicochemical properties and SwissADME values.