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scientific challenge

fall 2020 challenge launched
submit your proposal until August 24th

news of the week

Here is one of the projects that made it into the summer 2020 challenge:

Computer-aided drug design & Computational chemical biology

Computational approaches to block SARS-CoV-2 entry
Since the first time it was observed in the late 2019, COVID-19 has spread as a very dangerous pandemic which has led to a new emergency state all over the world and, moreover, it has become in an issue for all the health care systems. COVID-19 syndrome is caused by a RNA virus (SARS-CoV-2), which has motivated the research of vaccines as main therapeutic approach. However, the virus presents high and complex glycosylation patterns which makes it difficult to develop an effective vaccine. Moreover, viruses are meant to mutate along their life cycle, reducing the efficacy of this treatment. A key point for the infection is the interaction through the RBD motive on the virus spike protein with ACE2 receptor to mediate the virion internalization. Our aim is to study this protein-protein interaction to find a new source of small molecules as potential antivirals for the treatment of this disease as a novel approach to overcome the drawbacks of vaccine development.
"We intend to achieve the following milestone(s):
  1. By means of the novel application of Protein Editor mode in SeeSar we will mutate residues in the dimerization interface to study their roles
  2. Looking for binding sites using DoGSiteScorer and we will start to dock our personalized libraries of antiviral compounds using FlexX
  3. Docking of new libraries (including marketed drugs) and scaffold hopping approaches by means of ReCore for further synthesis"
— Javier García Marín, Centro de Investigaciones Biológicas Margarita Salas, Spain

Javier will be using SeeSAR, infiniSee, PepSee, FlexX, ReCore, HYDE, PoseView, REAL Space Navigator, SMARTSeditor, Mona, and DoGSiteScorer.

current champion

The following project won the 'summer 2019' scientific challenge:

 
Structure-based drug design of selective Drp1 inhibitors for dementia treatment
Jessica Holien
St. Vincent's Institute of Medical Research, Fitzroy, Australia
Jessica Holien
St. Vincent's Institute of Medical Research
Fitzroy, Australia

Dementia

Structure-based drug design of selective Drp1 inhibitors for dementia treatment
Jessica summarizes:
The mitochondrial protein dynamin-related protein (Drp1) has been implicated in the development of a number of neurodegenerative diseases, including Alzheimer’s disease. To date, no direct small molecule inhibitors of human Drp1 have been identified. A year ago, we started this project with three "hit" compounds (OB-27, OB-37 and OB-47), from three alternate chemical classes, which interacted with Drp1 directly and inhibited its activity in cell-based assays. Using FTrees to search for compound analogues, we found 100 analogues to purchase/synthesise for each compound class. Using SeeSAR to dock and rank the compounds, we purchased 64 analogues. Surface plasmon resonance (SPR) assays showed that 19 of these compounds directly interacted with Drp1 in a dose-response manner (Kd range 3-520uM, notably 5 compound were insoluble and 13 compounds bound to SPR chip thus binding affinity could not be assessed). This gave us an adjusted hit rate (taking into consideration compounds which could not be assessed) of approx 53%. Importantly, 12 of these interacting compounds were from the same chemical class (OB-47 analogues). This result allowed us to focus our chemistry effort into this class of compounds. Using SeeSAR, we then designed 20 compounds predicted to have better activity than our lead compound, to synthesise and assay. Unfortunately, due to COVID-19, these studies have not yet been completed. In summary, BioSolveIt software assisted us in choosing compound analogues to purchase (giving an adjusted hit rate of approx 53%). The biological evaluation for these analogues led to a front runner compound series. BioSolveIT software was again used to design compounds of this series with improved activity.
The following goals have been achieved:
  1. Search for chemically similar compound analogues to purchase. FTrees was run, in the infinisee interface using the REALspace_2019-05 library on our top 3 compounds classes. The top 100 analogues were shown for each compound. I removed any compound analogues that I have already purchased and tested.
  2. Dock all compounds into our crystal structure and rank the best before purchasing Compounds were docked and analysed in SeeSAR, resulting in the purchase of 64 analogues. These were assayed giving an adjusted hit rate of approx 53%.
  3. Identify and improve a front runner compound series for medical chemistry effort. Assays identified a clear front runner series (13 active compounds). SeeSAR was then used to design 20 analogues for chemical synthesis.

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 2020 contest, please
    submit your proposal until August 24th 2020
  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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