scientific challenge

fall 2017 challenge launched
submit your proposal until August 24th

news of the week

Here is one of the winners of spring 2017 challenge's first three months:

Zika

Discovery of new inhibitors of Zika Virus NS3/NS2b protease
Gustavo reports:
We were able to validate FlexX to selectively discriminate possible ligands to the ZIKV NS3-NS2b protease. We have also run a long MD simulation of the protein, which evidenced this system's large flexibility. This flexibility must be considered when scanning the databases. We will do so by using the FlexE ensemble docking module, with structures obtained from clustering the MD trajectory. DIFFICULTIES ENCOUNTERED: DATABASES. The FDA-approved database as >8,000 compounds. However, many of those lack or have invalid structural information. Since LeadIT requires all the molecules in the database to be in 3D format with hydrogens, it was necessary to adapt the databases accordingly. We are still in this process. Meanwhile, we are using a smalled database from DrugBank. FlexE. At the moment, we are still learning to use the FlexE ensemble docking module. I have contacted the BioSolveIT help for a working example that we could use as a starting point for our simulations.
The following milestones have been achieved:
  1. Analyze known ligands for method validation
    REDOCKING. The receptor was prepared in LeadIT, and the active site was chosen to include all residues within 12 Å of any inhibitor atom. For docking, the boron atom type was replaced by a C.3 type. The highest scored conformation had a RMSD 5.1 Å to the original ligand before optimization, and 1.5 Å after, indicating that the docking followed by optimization is capable of finding the native solution. KNOWN LIGANDS. We used a selection of 10 known ligands of NS3-NS2b with measured IC50 from the literature. The experimental IC50s are all in the micromolar range. We used MarvinSketch to generate all possible ligand tautomers, then docked each to the same active site as above using FlexX in the LeadIT graphical environment. All tautomers docked satisfactorily. Furthermore, the number of tautomers for each ligand docked with score below 20 kJ/mol shows a very good correlation to the IC50 ordering. Those results indicate that FlexX is able to discriminate active molecules from a database.
  2. Scan database of FD-Approved molecules to identify possible inhibitors
    TARGET: Given the dynamic nature of the ZIKV NS3-NS2b protease, it is important to consider the receptor flexibility while searching for active molecules. We used molecular dynamics to generate an ensemble of structures for the target. The trajectory was sorted into 30 different clusters. The large number of clusters is a consequence of the large flexibility of the target. A representative structure from each cluster was selected. LIGANDS: A database of 1,864 molecules approved for use in humans, plus 4,759 molecules in experimental phase was obtained from DrugBank. IN PROCESS: A detailed analysis of the interactions between the target and the known inhibitors will yield a pharmacophore model to filter the database for molecules with the most important features. The filtered database will then be scanned using ensemble docking in FlexE to select for potentially active molecules. The most promising molecules will be purchased and tested by our experimental virology collaborators.
  3. Suggest modification to optimize binding, to be later tested by collaborators
    This step has not started yet. The procedure above will reveal known molecules with inhibitory activity against ZIKV. However, since none of these molecules was specifically developed for this target, it is likely that the activities can be improved by targeted modifications on the structure. We plan to use HYDE/SeeSAR to analyze the ligands with best experimental activities to understand the important interactions they make with the receptor. Then, together with our experimental synthetic collaborators and the help of HYDE/SeeSAR, we will plan feasible modifications in the molecules likely to improve the activity. A set of new molecules will be generated and synthesized and tested experimentally again.

current champion

The following project won the 'summer 2016' scientific challenge:

 
Inhibitors of dextransucrase enzymes and the decrease of dextran content in the sugar
Reinaldo Fraga
Cuban Research Institute on Sugarcane By-Products (ICIDCA), Havana, Cuba

For more information please visit the hall of fame.

invitation

BioSolveIT is inviting academic teams, non-profit organizations and individuals to participate in an exciting Scientific Challenge: if you are working on a drug discovery problem, take advantage of BioSolveIT's wide array of software tools to meet your goals. How to participate? Just send us a proposal for the project you'd like to advance using BioSolveIT software. We will review every proposal very carefully and award the most attractive ones. A new contest starts every three months.

motivation

In a first phase, the most promising proposals will receive free BioSolveIT licenses for 3 months to con­duct the desired research. For phase II, the most interesting results are granted a free license extension by 9 months and we will sponsor the presentation of the overall best achievement with a travel grant of 1000€. For more details please read the terms of challenge.

procedure

  1. To enter the fall 2017 contest, please
    submit your proposal until August 24th 2017
  2. Based on scientific novelty, interest of target, and approach sought, we will select from all submissions the best, maximum 5 to enter the contest. Every participant will be informed of our decision by September 1st. These most promising projects will receive free fully functional licenses and support to all relevant BioSolveIT tools, valid for 3 months.
  3. After the initial 3 months the best, maximum 3 projects will receive another 9 months of free software access to BioSolveIT's entire software suite and premium support. And after 9 months, the overall best project will be rewarded with a travel grant of 1000€ to a high impact conference for a presentation of the results.

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