Interactions of Ganoderiol-f with Aspartic Proteases of Hiv and Plasmepsin for Anti-hiv and Anti-malaria Discovery

Objective: HIV-1 has been a killer disease since two decades ago, while a potential cure has not yet discovered due to the fast mutations of the HIV1 enzymes,i.e reverse transcriptase, integrase, and protease. Apart of HIV-1, malaria has been the biggest cause of death in human and it is mostly found in the East part of Indonesia. There are some enzymes in the food vacuole of Plasmodium falciparum which are the targets of anti-malaria discovery, e.g. plasmepsin I, II, IV, and histo-aspartic protease (HAP). Both plasmepsin and HIV-1 protease are aspartic proteases, therefore a single drug could be designed to inhibit both enzymes. Ganoderiol-F is a triterpenoid isolated from the stem of Ganodermasinensewhich shows inhibition on HIV-1 protease with IC50 20-40 μM. This project was aimed to study and visualize the interaction of ganoderiol-F with HIV-1 protease and plasmepsin I for anti-HIV and anti-malaria discovery. Methods: Preparation of the ligand comprises of geometry optimization using MM+ method and Polak-Ribiere (conjugate gradient) algorithm. Molecular docking using AutoDock 4.2 was used to put the ligand into the binding site of both aspartic proteases. Pepstatin-A was used as comparison. The amino acid residues near the drug-target interactions and affinity of the drugs were identified. Results: The affinity of ganoderiol-F is higher towards HIV-1 protease (binding energy= -11.40kcal/mol and Ki= 4.68nM) than to plasmepsin I (binding energy= -9.96 kcal/mol and Ki= 50.94 nM), meanwhile pepstatin-A has better affinity towards HIV-1 protease (binding energy= -4.52 kcal/mol and Ki= 496.13 μM) than to plasmepsin I (binding energy= -3.07 kcal/mol and Ki= 5.98 mM). Conclusions: According to the values of binding energy and inhibition constant, ganoderiol-F could be developed further as both anti-HIV and antimalaria.