Pharmacophore modeling, docking and molecular dynamics to identify Leishmania major farnesyl pyrophosphate synthase inhibitors

Abstract

Leishmaniasis is caused by protozoa of the genus Leishmania spp. and is considered the second most important protozoa in the world due to the number of cases and mortality. Despite its importance in terms of public health, the treatment of patients is limited and has mostly low levels of efficacy and safety. Farnesyl pyrophosphate synthase (FPPS) acts in the early stages of isoprenoid synthesis, and is important for maintaining the integrity of the lipid bilayer of the parasite that causes the disease. The aim of this work was to identify one potential inhibitor of the FPPS of Leishmania major through virtual screening by pharmacophore modeling and docking. A total of 85,000 compounds from a natural products database (ZINC15) was submitted for virtual hierarchical screening, and the top ranked molecule in both methods was analyzed by intermolecular interaction profile and 20ns molecular dynamics simulations. These results showed a promising compound from natural products that mimic the major interactions present in the substrate/inhibitor.