Drug search for leishmaniasis

a virtual screening approach by grid computing

Rodrigo Ochoa, Stanley Watowich, Andrés Flórez, Carol V. Mesa, Sara M. Robledo, Carlos Muskus

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The trypanosomatid protozoa Leishmania is endemic in ~100 countries, with infections causing ~2 million new cases of leishmaniasis annually. Disease symptoms can include severe skin and mucosal ulcers, fever, anemia, splenomegaly, and death. Unfortunately, therapeutics approved to treat leishmaniasis are associated with potentially severe side effects, including death. Furthermore, drug-resistant Leishmania parasites have developed in most endemic countries. To address an urgent need for new, safe and inexpensive anti-leishmanial drugs, we utilized the IBM World Community Grid to complete computer-based drug discovery screens (Drug Search for Leishmaniasis) using unique leishmanial proteins and a database of 600,000 drug-like small molecules. Protein structures from different Leishmania species were selected for molecular dynamics (MD) simulations, and a series of conformational “snapshots” were chosen from each MD trajectory to simulate the protein’s flexibility. A Relaxed Complex Scheme methodology was used to screen ~2000 MD conformations against the small molecule database, producing >1 billion protein-ligand structures. For each protein target, a binding spectrum was calculated to identify compounds predicted to bind with highest average affinity to all protein conformations. Significantly, four different Leishmania protein targets were predicted to strongly bind small molecules, with the strongest binding interactions predicted to occur for dihydroorotate dehydrogenase (LmDHODH; PDB:3MJY). A number of predicted tight-binding LmDHODH inhibitors were tested in vitro and potent selective inhibitors of Leishmania panamensis were identified. These promising small molecules are suitable for further development using iterative structure-based optimization and in vitro/in vivo validation assays.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalJournal of Computer-Aided Molecular Design
DOIs
StateAccepted/In press - Jul 20 2016

Fingerprint

Leishmaniasis
Grid computing
Leishmania
Screening
drugs
screening
proteins
Proteins
Molecular Dynamics Simulation
Pharmaceutical Preparations
Molecular dynamics
Molecules
molecular dynamics
death
Skin Ulcer
Molecular Conformation
inhibitors
Conformations
Protein Databases
Protein Conformation

Keywords

  • Drug discovery
  • Grid computing
  • Leishmania
  • Relaxed Complex Scheme

ASJC Scopus subject areas

  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Computer Science Applications

Cite this

Drug search for leishmaniasis : a virtual screening approach by grid computing. / Ochoa, Rodrigo; Watowich, Stanley; Flórez, Andrés; Mesa, Carol V.; Robledo, Sara M.; Muskus, Carlos.

In: Journal of Computer-Aided Molecular Design, 20.07.2016, p. 1-12.

Research output: Contribution to journalArticle

Ochoa, Rodrigo ; Watowich, Stanley ; Flórez, Andrés ; Mesa, Carol V. ; Robledo, Sara M. ; Muskus, Carlos. / Drug search for leishmaniasis : a virtual screening approach by grid computing. In: Journal of Computer-Aided Molecular Design. 2016 ; pp. 1-12.
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