Identification of potential antileishmanial agents via structure-based molecular simulations

Leishmaniasis is a parasitic disease with frequent annual incidence. An important issue in chemotherapy is the emergence of resistance, toxicity and lack of cost-effectiveness within current drugs. Therefore, it is of utmost importance to design effective drugs against disease. Current contribution was devoted to the in-silico analysis of binding a few flavonoids/alkaloids to relevant leishmanial targets. Docking scores were used to prioritize acquired affinities and top ranked binders were subjected to subsequent 100-ns MD simulation in explicit water. Binding trajectories revealed the tightest interaction modes for two flavonoid molecules (acerosin and nevadensin) in the uracil DNA glycolase (UDG) active site. Acerosin showed less conformational changes whereas, nevadensin interacted stably during longer simulation time. Conserved interactions of Gln205 and His331 to acerosin indicated their dominant biological role in complex stability. No conserved residues were perceived for nevadensin interactions and a completely new and stable binding conformation could be retrieved after 12 ns simulation. Moreover; acerosin was subjected to DFT analysis for pairwise decomposition evaluations of interacted residues. Although primary mechanisms of action are yet to be discovered, UDG may be a promising target for developing antileishmanial flavonoids.