The Octahydroindene Carboxyl Substructure from Dihydrobetulinic Acid is Essential to Inhibit Topoisomerase IB fromLeishmania donovani

Camila A Rocha,Paulo R S Sanches,Reinaldo Marchetto,Aderson Zottis

doi:10.5935/0103-5053.20150295

Camila A Rocha, Paulo R S Sanches + Show 2 more

Open Access

https://doi.org/10.5935/0103-5053.20150295

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Abstract

The dihydrobetulinic acid is a known competitive inhibitor of topoisomerase IB from Leishmania donovani, a validated target for developing new antileishmanial drugs. However, its binding mode and interaction pocket have not been established yet. We combined docking and molecular dynamics simulations to identify the most probable binding pocket. Our best model strongly suggests a cavity involving the residues arginine 314 and arginine 410 from chain A, and the catalytic tyrosine 222 from chain B as the interaction site and a substructure of this terpene inhibitor as essential for the process of molecular recognition. Then, a new class of inhibitors with increased affinity could be designed by structure-based approaches.

Highlights

Visceral leishmaniasis disease (VL) or Kala-azar is the second largest parasitic killer in the world and infects an estimated 200-400 thousand people each year.[1,2] VL is caused by the Leishmania donovani (L. donovani) protozoan and transmitted by phlebotomine sand flies
For the first pocket, the H-bonds formed between the carboxyl from dihydrobetulinic acid (DHBA) and the side chains of the arginine 314 (ARG314) from chain A and tyrosine 222 (TYR222) residues were previously identified by docking
The carboxyl group showed a great change in its position to follow interactions with the side chains of ARG314, arginine 410 (ARG410) and TYR222, accounting for the most hydrophilic forces keeping the DHBA-topIB

Summary

Introduction

Visceral leishmaniasis disease (VL) or Kala-azar is the second largest parasitic killer in the world (only malaria is more fatal) and infects an estimated 200-400 thousand people each year.[1,2] VL is caused by the Leishmania donovani (L. donovani) protozoan and transmitted by phlebotomine sand flies. The carboxyl group showed a great change in its position to follow interactions with the side chains of ARG314, ARG410 and TYR222, accounting for the most hydrophilic forces keeping the DHBA-topIB

Results

Conclusion