Leishmaniasis is a group of Neglected Tropical Diseases (NTDs) which are present in around 88 countries on tropical and subtropical regions worldwide. The current treatments against these diseases present several problems such as low effectiveness, resistance, and high toxicity. More than 50% of new small molecules approved in U.S. are related with natural products, being these interesting alternatives very important in the search of new efficient and safety treatments for this group of diseases. Kauranes (diterpenes) have presented potential biological activities highlighting some molecules that have anticancer properties; however, this type of compounds has not yet been studied deeply against Leishmaniasis. In this study, hybrid homology models for an important target of Leishmania, Dihydrofolate reductase – thymidylate synthase (DHFR-TS) were constructed using YASARA software. This test enzyme was related to three species, L. panamensis, L. amazonensis and L. braziliensis, whose incidence is responsible by causing Leishmaniasis in Central and South America. In parallel, a database of 360 kaurane-type structures was constructed and all 3D structures were minimized using a MM2 force field. Thus, molecular docking studies, using the entire database were performed using autodock/vina. Best docking scores resulted between 10.85 and 10.96 kcal/mol, involving RMSD values below 1, even better than pteridine-related compound used as control. Structural features were then identified to be crucial by multivariable analysis and used to establish a Structural-Activity relationship for this kaurane-type set. The compound 3α-cinnamoyloxy-ent-kaur-16-en-19-oic acid exhibited the best docking result for Lp and LbDHFR-TS and it also was part of the best five-ranked compounds for LaDHFR-TS. Finally, using GROMACS package, molecular dynamics simulations were therefore performed to validate the docking findings through the physical movements and evolution of the enzyme-ligand complexes over the time.
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IN SILICO STUDIES TO EVALUATE INTERACTIONS BETWEEN KAURANE-TYPE DITERPENES AND THE DIHYDROFOLATE REDUCTASE – THYMILIDINE SYNTHASE OF THREE LEISHMANIA SPECIES.
Published: 25 October 2018 by MDPI in MOL2NET'18, Conference on Molecular, Biomed., Comput. & Network Science and Engineering, 4th ed. congress CHEMBIOMOL-04: Chem. Biol. & Med. Chem. Workshop, Paraiba, Porto, Rostock, Germany-Galveston, Texas, USA, 2018
Keywords: Leishmania; molecular docking; kauranes; in silico; molecular dynamics.