Team leader Dr. Carlos Muskus provided this extensive update on the progress of the Drug Search for Leishmaniasis project.
The near future
- Our result filtering procedure is nearly finished, with approximately 96% of the data processed. This part of the project should be finished in the next 2 or 3 weeks. For more details, see the results section below.
- A paper including the results is almost ready to be submitted for publication to an international journal. We are waiting for complete filtering results, but expect to submit the paper before the end this of year.
- Within the past year, I have had the opportunity to present the DSFL project results in different local, national and international contexts, including WorldLeish5 in Brazil, the International Congress of Parasitology in Mexico City, and the XII International Congress of Microbiology, in Cartagena-Colombia.
- Other members of the DSFL team and I are helping organize the Third Colombian Congress on Computational Biology and Bioinformatics, to be held next September in Medellin. This will be a great opportunity to publicize the results of the DSFL project in deeper way and to promote World Community Grid.
- We are planning a second phase of the project which will be focused on determining how strong the interaction is between ligand and receptor. This bond can be determined by using the Binding Energy Distribution Analysis Method (BEDAM) program or another similar program.
Detailed results
The last year of work really helps emphasize the tremendous scale of our project. World Community Grid volunteers generated approximately 4TB of data, consisting of more than 1.5 billion records, which store information about interaction energies between a set of Leishmania proteins and a library of 600,000 compounds. During the data recompilation, a procedure was executed to filter and organize the most relevant data. A relational database was built with information about the targets, the models (snapshots of the initial set of proteins) obtained from the molecular dynamics (MD) simulations, the compounds, and the interaction energy scores between the molecules involved. The goal of this first phase was to rank and choose the best candidates based on meta-analyses which could identify the most suitable ligands for subsequent experimental validations.
We have found some particular proteins that have been studied widely as potential molecular targets. Some of them have produced interactions with simulated free energies around -13 kcal/mol (Table 1), molecular complexes with potentially higher affinities between the external ligands and the parasite proteins.
Table 1. List of compounds and proteins targets, including the model number obtained by MD simulations, with the better interaction energy scores.
| Score (kcal/mol) | Compound | Target (PBD code) | MD Model (10 per target) |
| -13,8 | ZINC05835XXX | 3P0I | 20 |
| -13,3 | ZINC33122XXX | 3MJY | 50 |
| -13,1 | ZINC05835XXX | 3P0I | 10 |
| -13 | ZINC12210XXX | 3P0I | 10 |
| -13 | ZINC08591XXX | 3MJY | 50 |
| -13 | ZINC21173XXX | 3MJY | 50 |
| -13 | ZINC21887XXX | 3MJY | 10 |
| -12,9 | ZINC33140XXX | 2RQ8 | 40 |
| -12,8 | ZINC12097XXX | 2HFU | 20 |
| -12,8 | ZINC09319XXX | 3MJY | 50 |
Based on the preliminary results, we are optimistic about finding a good candidate to treat leishmaniasis, which can be improved with further computational and experimental validations. We are preparing for a second phase of the project, which involves an extra selection filter using an adapted MD protocol to avoid false positives and consequently detect molecular hits that can behave similarly to real life. With the help of all the volunteers we hope to identify at least one new molecule capable of fighting against a neglected disease that urgently needs more effective and non-toxic chemical treatments.
Currently the data are still under analysis in our servers. We are still filtering the best docking results. Once we analyze the data and extract the needed information, we will release the data.
Lab-based testing and confirmation
Now that we have nearly finished analyzing the simulations of potential compounds, we need to move to real-world testing to confirm our predictions. This requires considerable funding for lab time and materials. Unfortunately, we have had difficulty securing funding to perform this in vitro testing - we have made applications for funding from several organizations, including the Tres Cantos Open Lab Foundation and the Pathogen Box. To date, these have been unsuccessful, so we are not yet able to perform in vitro testing of all the compounds we would like to test. However, the main Colombian funding agency (Colciencias) approved funds to test between 10 and 20 compounds. Ten of the most promising compounds have been already purchased and are being tested in our lab. The best of these will be evaluated in animals before testing in clinical assays, if any.
Thank you to our collaborators
And finally, we want to say a huge thank-you to some of the collaborators who have helped us throughout this process.
Working with World Community Grid for over three years has been a fantastic experience. Since the beginning of the project in September 2011, we have maintained a tight relationship with the team at World Community Grid. And of course, the volunteers who donated their computing time made this entire project possible—we can’t say thank you enough for that generosity.
Since the beginning of the DSFL project, Dr. Stan Watowich of the University of Texas Medical Branch has been an invaluable collaborator for us. In fact, Rodrigo Ochoa (one of the members of the PECET team) learned how to run docking in his Lab in Galveston-Texas. Besides Dr. Watowich, Drs. Juan Guillermo Lalinde and Juan David Pineda, from the University of EAFIT, also in Medellin Colombia have provided extensive support to the project, providing a lot of computer time in the University of EAFIT with the Apollo-cluster. Since this collaboration, we have continued working together on this and in other projects involving computational processes.
Finally, we started communication with Dr. Olson´s Lab at The Scripps Research Institute in La Jolla, California. They have a lot of experience in drug discovery, and are the developers of AutoDock Vina, the program we use in the DSFL project. Their BEDAM program may allow us to filter our results further based on thermodynamic parameters.
Other team news
Andres Flórez, one of the PECET team and currently in Heidelberg-Germany conducting his PhD, won a competition of science dance. They had to represent the doctoral thesis by means of arts, basically through dance. The name of his work was, “Understanding the Role of MYCN in Neuroblastoma using a Systems Biology Approach".
Rodrigo Ochoa got an international award for a computational tool developed at the European Molecular Biology Lab during an internship in Hinxton-England. In August 10-14 this year, Rodrigo was invited to present his work in San Francisco, California in one of the biggest events of science: 248th ACS National Meeting & Exposition. (American Chemical Society).
We had a technical problem with our PECET Lab web site and most of the information regarding this project on our web page was lost along with the PECET information. We are working to restore the information soon.