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scientific challenge

winter 2018 challenge launched
submit your proposal until November 23rd

news of the week

Here is one of the winners of spring 2018 challenge's first three months:

Chronic Pain

Identification of selective non-opioid small molecule analgesics by targeting Nav1.7
Sharat reports:
Voltage-gated sodium (Nav) channels act as molecular targets of cardiovascular and neurological disorders. We are targeting the Nav1.7 found in the peripheral nervous system and involved in pain perception. In this study, we designed an integrated ligand- and structure-based virtual screening procedure for the identification of isoform-selective antagonist of Nav1.7, by utilizing the recently identified class of isoform-selective antagonist data. Initially, a similarity search was performed and the identified hits were docked into a binding site on the fourth voltage-sensor domain, VSD4. We used FTrees tool for similarity searching and library generation, the generated library was docked using FlexX and compounds were shortlisted using FlexX score and SeeSAR hyde scoring. Finally, the top 25 compounds were tested with Molecular dynamics simulation (MDS). Using MDS RMSD plot we have narrowed down our list to 10 compounds and are ready to proceed with in-vitro experiments.
The following milestones have been achieved:
  1. A library of compounds will be generated
    The database containing 1.5 million compounds from ChemDiv library (ChemDiv Inc., San Diego, CA) was utilized for in silico similarity searching. The idea behind this approach is to find similar compounds to those already known for VSD4 active site binders. By immobilizing the S4 helix of VSD4, Nav channel inhibition is achieved by the voltage-sensor trapping mechanism. We used three known Nav antagonists Funapide, PF-05089771, and GX-936 as query molecules against ChemDiv database. Therefore, a library of 2000 compounds was designed based on Global similarity score as well as local similarity score of aryl sulfonamide group. The reason for the focus on aryl sulfonamide is that these inhibitors are directly involved in the interaction with the fourth gating charge residue on the voltage-sensing S4 helix and effectively trap VSD4 in its activated state.
  2. A list of top hits based on molecular docking experiment
    As mentioned, the aryl sulfonamide inhibitors directly engage the fourth gating charge residue (R4). Further, the isoform-specific inhibitor can be designed by targeting the non-conserved residues found on the S2 (YWxxV) and S3 (GMxxA) transmembrane helices. Therefore, the active site for docking experiments was delineated by selecting these residues and the generated library of 2000 compounds from the first milestone was docked into this site using FlexX module. After performing the docking experiments, we analyzed all the docked complexes to identify those compounds, which are making significant interactions with the fourth gating charge residue (R4) and other residues imparting isoform selectivity. The compounds were also assessed for ligand affinity with HYDE in SeeSAR for further validation. After analysis, a list of 25 compounds was prepared to perform MD simulations.
  3. A list of compounds validated via MD Simulation
    The binding site for Nav1.7 is partially surrounded by membrane bilayer. It has been observed that a bound phospholipid forms a trimeric complex with the inhibitor and the channel protein. Therefore, we have performed a series of membrane simulations of Nav1.7 in complex with identified compounds. These complexes were subjected to 50 ns simulation using OPLS-2005 forcefield. We have investigated the RMSD of the ligands with respect to protein. The complexes whose values for ligand RMSD were lower than the protein RMSD were further selected. We have also monitored the protein interactions with the compounds throughout the simulation by analyzing the occupancies of protein-ligand contacts. Those compound-complexes where the interaction between the ligand and R4 were maintained throughout the simulation time were kept for further consideration. Based on these analysis, we have shortlisted a set of 10 compounds to undergo biological evaluation.

current champion

The following project won the 'fall 2017' scientific challenge:

 
Dual action agent: activator of glucokinase and inhibitor of dipeptidyl peptidase-4
Nadezhda Demina
Ural Federal University, Ekaterinburg, Russian Federation
Nadezhda Demina
Ural Federal University
Ekaterinburg, Russian Federation

Diabetes mellitus type 2

Dual action agent: activator of glucokinase and inhibitor of dipeptidyl peptidase-4
Nadezhda summarizes:
For 12 months of fruitful work we have been able to find out the key factor causing the pharmacological activity of the ligand, to design a molecule with potential activity for both glucokinase and a-glucosidase, and to synthesize and test this compound. In the course of our work, the two programs have become indispensable helpers: LeadIT has helped us to reveal the regularity in the ligand's manifestation of biological activity, and with the help of SeeSAR we constructed dual action agent, which was confirmed by biological tests.
The following goals have been achieved:
  1. To understand the key ligand-receptor interactions that cause pharmacological activity. This is extremely important in the development of the glucokinase activator, since the regulation of the enzyme is carried out through the allosteric center. We used LeadIT soft for docking more than 50 known glucokinase activators, as well as previously developed by us compounds with different activity against glucokinase, and compared the set of amino acids to which each of the compounds binds using 2D diagrams. This allowed us to find out that the necessary condition for an active compound is its ability to interact with Arg63 of the binding site. It was the key data for our further research.
  2. To create a molecule with potential activity for both glucokinase and a-glucosidase. No doubt the most effective tool for implementing this goal is the SeeSAR program. We sequentially built the backbone of the molecule, using two proteins as a reference point, and then modified the resulting scaffold to achieve the best affinity indices in both cases. So we were able to achieve pM affinity for glucokinase and nM one for a-glucosidase.
  3. To confirm results in practice. We synthesized 20 molecules with minor modifications of the leader compound. The assembly of the created scaffold was more complicated than we expected, and was associated with the development of new synthetic approaches. All obtained compounds were sent for biological studies. Unfortunately, at the time of writing this report, we received data only for one of the substances. The test substance showed activity superior to the reference compound in the case of glucokinase and statistically significant inhibits the a-glucosidase.

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 winter 2018 contest, please
    submit your proposal until November 23rd 2018
  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 December 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.