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scientific challenge

summer 2019 challenge launched
submit your proposal until May 24th

news of the week

Here is one of the projects that made it into the spring 2019 challenge:

Cancer

Target-based and Ligand-based approach to design novel allosteric CD73 inhibitors
CD73 is overexpressed on cancer and immune cells. This enzyme attached to the extracellular cell-surface catalyzes the hydrolysis of AMP into adenosine (ADO) and inorganic phosphate and therefore participates actively in the accumulation of high level of ADO in the tumor microenvironment. CD73-generated ADO has been shown to promote cancer progression and metastasis. In this context, we develop new CD73 allosteric inhibitors using a combined approach: Target-based design to identify CD73 inhibitors. For this purpose, an allosteric site identified in the dimeric enzyme will be used for virtual screening of public chemical libraries. Second, a Ligand-based design will be used to improve the activity of existing allosteric compounds by generating a 3D pharmacophore specific to the allosteric cavity. Results of virtual screening will be validated by an in-house in-vitro test
"We intend to achieve the following milestone(s):
  1. Allosteric pharmacophore modeling & screening
  2. Allosteric molecular docking
  3. Crossing virtual screening results and new hits identification"
— Abdennour Braka, IRIM - UMR 9004 - CNRS, France

Abdennour will be using SeeSAR, CoLibri, PepSee, LeadIT, FlexX, ReCore, HYDE, FlexS, FTrees, FTrees-FS, PoseView, REAL Space Navigator, KNIME® Interfaces, SMARTSeditor, SMARTSviewer, TorsionAnalyzer, Mona, and DoGSiteScorer.

current champion

The following project won the 'spring 2018' scientific challenge:

 
Identification of selective non-opioid small molecule analgesics by targeting Nav1.7
Sharat Chandra
Center for Translational Pain Medicine, Department of Anesthesiology, Duke University, Durham, United States
Sharat Chandra
Center for Translational Pain Medicine, Department of Anesthesiology, Duke University
Durham, United States

Chronic Pain

Identification of selective non-opioid small molecule analgesics by targeting Nav1.7
Sharat summarizes:
Since last 12 months, with the help of Biosolveit software we have identified a novel chemical scaffold which acts as a potent inhibitor of human voltage-gated Na+ ion channel Nav1.7 for the treatment of pain. Chronic pain (CP) is a disease that results from an injury or a disease that affects the somatosensory nervous system. CP is gradually becoming a serious global health problem. Approximately 10-55% of the world’s population is suffering from chronic pain. In addition, the cost of treating chronic pain is enormous, which imposes a huge burden on health budgets. Therapeutic approaches for chronic pain have limited effectiveness. As a result, physicians prescribe opioids for chronic pain, which leads to an epidemic of opioid prescription, abuse and addiction. Thus, the development of novel, effective and safe drugs for CP is still an unmet medical need. Voltage-gated sodium (Nav) channels act as molecular targets of cardiovascular and neurological disorders. It is difficult to design selective inhibitor of Nav channels because there are nine closely related isoforms (Nav1.1 - 1.9) that share high sequence identity. We are targeting the Nav1.7, which is found in the peripheral nervous system and involved in pain perception. A new class of analgesics targeting voltage-gated sodium channels (Nav) could help to treat people with CP. Before applying for the Biosolveit challenge we obtained some preliminary data, in which we have standardized molecular dynamics simulation (MDS) experiment with positive and negative control and a few docked compounds from a small compound library. Then our next objective was to screen 1.5 million compound library for identification of inhibitor for Nav1.7 with analgesics effect. We have developed this project with the computational support of Biosolveit software. In this study, we designed a protocol for the identification of isoform-selective inhibitor of Nav1.7, by utilizing the 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 the FTrees tool for similarity searching and library generation, the generated library was docked in the VSD4 domain binding site using FlexX and compounds were shortlisted using a FlexX score and SeeSAR hyde scoring. Finally, the top 25 compounds were tested with MDS. On the basis of MDS RMSD plot we have narrowed down our list to 9 compounds and purchased them for in vitro and in vivo validation. These experiments have led to identify a novel compound with good activity and a very interesting IC50 value (0.74 µM). With same cycle of above methods, we have started optimization of our novel lead compounds.
The following goals have been achieved:
  1. ‘Accomplished Virtual Screening and in silico validation’. The database containing 1.5 million compounds was utilized for in silico similarity searching. We used known Nav antagonists PF-05089771, and GX-936 as query molecules against compound database. Therefore, a library of 2000 compounds was designed based on the Global similarity score as well as local similarity score of aryl sulfonamide group. It was shown in previous studies that 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 were docked into this site using FlexX module. 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 MDS.
  2. ‘Hit identification’. 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 force field. The final Nav1.7-compound complex of each MDS setup were re-evaluated by SeeSAR and HYDE. The complexes whose values for ligand RMSD were lower than the protein RMSD were selected for further assessment. Based upon these analysis, we have purchased a set of 9 compounds to undergo biological evaluation.
  3. ‘In vitro and in vivo confirmation of compounds’. Whole-cell patch-clamp recordings in HEK-293 cells and DRG neurons were conducted. We used patch pipettes to record transient Na+ currents. One of the compound dose-dependently reduce the peak sodium currents in Nav1.7-HEK-293 stable cell line, with an IC50 values at 0.74 µM. At 10 µM concentration of lead compound has a weak inhibitory effect on the sodium currents in both mouse and human DRG neurons. We also tested whether lead compound could attenuate formalin-induced inflammatory pain following spinal intrathecal route via lumbar puncture. Intrathecal injection of 10 nmol has a weak anti-nociceptive effect in the second phase of formalin test. Our findings suggest that lead compound have some effect in reducing pain. We plan to proceed with optimization of the lead compound to improve its efficacy and to reduce the IC50 values.

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 summer 2019 contest, please
    submit your proposal until May 24th 2019
  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 June 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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