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Exceptional early results in the fight against Leishmaniasis
By: Dr. Carlos Muskus López
Coordinator, Molecular Biology and Computational Unit, PECET University of Antioquia
12 Jul 2015   

Summary
The Drug Search for Leishmaniasis team has completed in vitro lab testing of the 10 top-rated compounds identified during screening, and have found that 4 of those 10 have very interesting properties that could point the way to new therapies. The post-processing of results continues, with the hope of identifying even more promising compounds for future lab and in vivo testing.

Last year, we updated you on the progress our team has made in filtering the computational results from our time on World Community Grid and identifying promising candidate compounds to test in the lab. Since then, we have completed the filtering process and identified over 100 compounds that the simulations predicted should bind effectively to the target PDB:3MJY protein in the Leishmaniasis parasite. However, the only way to be certain is to move those compounds into in vitro testing. Due to limited funding, we focused on the 10 compounds with the highest predicted rating, and found that 4 of them do in fact show positive results in in vitro tests, with one showing an exceptionally promising result. This means that in vitro the compounds kill the parasites efficiently while not affecting human cells.

Table 1. In vitro results from 4 of the best selected compounds against the protein PDB:3MJY according to the virtual screening strategy

Compound Cytotoxicity (LC50) Antiparasite (EC50) Selectivity (IS)
3MJYsZ04 7.5 ± 1.1 1.6 ± 0.3 4.7
3MJYcZ03 >200 19.2 ± 2.3 >10.4
3MJYcZ10 >200 13.4 ± 1.0 >14.9
3MJYcZ01 >200 0.7 ± 1.0 >285.7
Amphotericine B 42.1 ± 2.0 0.04 ± 0.01 1052.5


The compound 3MJYcZ01 is a very good candidate, and will be evaluated and optimized in further experiments. The results of these tests form the basis of a paper we’re presently finishing and about to submit to an academic journal.

Due to the high success rate of our screen (i.e. 40% of the compounds we tested showed good in vitro results), we think it would be very worthwhile to test the remaining compounds that we identified in our original screen, and we are still seeking funding to make that possible. In addition, the next step for the compounds already tested in vitro is to move to in vivo testing, and this process requires additional time and money. Unfortunately there are no crowdsourced initiatives like World Community Grid that can support actual in-lab testing!

Supporting the research community

Another important aspect of our work is making the results available to other researchers, so we have already presented our findings at both national and international events. Furthermore, we plan to present a full round-up of our work at the 3rd Colombian Congress on Computational Biology and Bioinformatics, in Medellin, in September 2015. To accommodate those who cannot attend, we will provide access to a public database with the respective affinity predictions for all the receptors and compounds analyzed, after the paper publication and the experimental validations of some hits.

In addition, one of the graduate student members of our team is planning to use pharmacokinetics and pharmacodynamics models and simulations to analyze several of the promising anti-leishmanial compounds. This will allow us to computationally predict the availability and distribution of the compounds in the human body. However, this evaluation will depend on public availability of pharmacological data of the compounds, and the quality of some predictions.

Team news

As our project carries on from year to year, it is inevitable that some team members will reach personal milestones along the way.

Andres Florez is finishing his PhD in Germany and is applying for a Post doc in Netherlands. Rodrigo Ochoa has finished his Master’s study and is currently working on measuring the stability of interactions between test compounds and the Leishmania protein.

Thank you

As we continue with our research, we’re constantly reminded of how valuable it is to have received such support from World Community Grid volunteers. Thank you for helping the fight against Leishmaniasis; we hope to have future work that can benefit from volunteer computing as well.


 


Project Update

Dr. Carlos Muskus López
Coordinator, Molecular Biology and Computational Unit, PECET University of Antioquia