Abstract

Visceral leishmaniasis is a neglected endemic disease caused by the intramacrophage obligate parasite, Leishmania donovani that affects millions of people worldwide. Visceral leishmaniasis treatment options have a number of issues in terms of effectiveness, cost, and side effects. Leishmania donovani adenosylmethionine decarboxylase (LdAdoMetDC) is a polyamine biosynthetic enzyme that is involved in the synthesis of spermidine. It is a potential therapeutic target for drug development against visceral leishmaniasis. In this study, computational methods have been used to gain insight into the inhibition of LdAdoMetDC. A library of phytochemicals from plants with antileishmanial activities and known inhibitors has been created. Homology modeling has been performed to determine the three-dimensional structure of LdAdoMetDC. Potent phytochemical inhibitors have been screened using virtual screening based on docking binding affinities. Furthermore, molecular dynamics simulations of docked complexes over 100 ns have been performed to assess docked complex stability. The binding free energy has been calculated using the molecular mechanics Poisson- Boltzmann surface area (MM-PBSA) method. The physicochemical properties of docked phytochemicals have been predicted in silico to assess their drug-likeness. CID5488537 (Fagopyrine), CID442630 (Carpaine), and CID44558930 (Anabsinthin) have been identified as lead molecules for targeting LdAdoMetDC.

Key words: Visceral leishmaniasis, Kala-azar, Leishmania donovani, Adenosylmethionine decarboxylase, medicinal plants, phytochemicals