Malaria predominantly affects millions annually in the African and Asian tropical and subtropical countries. With no effective vaccine, malaria prevention is exclusively dependent on preventing human-vector interaction. Anopheles gambiae, the main vector of the malaria parasite Plasmodium falciparum contains Odorant Binding proteins (OBPs) which are considered an attractive drug target for anti-malarial therapy. To identify a potential anti-malarial compound, we performed a structure-based screening of 876 phytocompounds derived from essential oils against the OBP4 by molecular docking. The compounds having better docking scores were assessed for drug-likeness, toxicity, and molecular interaction analysis. As per the results, strong affinities and high stability were demonstrated by two phytocompounds viz. Alpha-cyperone (-8.1 kcal mol-1) and Humulene oxide (-8.1 kcal mol-1) with OBP4. The hydrophobic interactions involve Phe123, Ala106, Thr57, Ala52, Thr69, and Ile64 within the binding cavities, which may block the OBP4 receptor resulting in disorientation. After that, the potential compounds were subjected to molecular dynamics (MD) simulation to evaluate their structural stability and dynamics at the active site of OBP4. The MM-PBSA result revealed that Alpha-cyperone and Humulene oxide had binding free energy of -92.44 kJ mol-1 and -113.25 kJ mol-1, respectively. Simulation outcomes demonstrate that these phytocompounds displayed considerable significant structural and pharmacological properties. The LD50 value of Alpha-cyperone and Humulene oxide also suggested that both are safe and suitable for use in natural repellent development. We suggest that the use of these compounds can minimize the treatment period and the various side effects associated with the currently available anti-malarial drugs.Communicated by Ramaswamy H. Sarma.
Keywords: MD simulation; Plasmodium falciparum; essential oils; molecular docking; mosquito repellent.