Here is one of the projects that made it into the winter 2019 challenge:
Ahmed will be using SeeSAR, infiniSee, CoLibri, FlexX, ReCore, HYDE, FlexS, FTrees, PoseView, REAL Space Navigator, KNIME® Interfaces, TorsionAnalyzer, and DoGSiteScorer.
The following project won the 'winter 2018' scientific challenge:
Aryl hydrocarbon Receptor (AhR) represents a network hub of genomic and non-genomic signaling pathways, which connects environmental factors to immune system. In physiologic conditions, this receptor mediates important effects on immune system, cancer development and cell cycle regulation. Interestingly, AhR-mediated effects are species-, tissue- and ligand- specific, leading to extend the paradigm of functional selectivity also for this transcription factor. In other words, different ligands can induce, selectively, a specific receptor conformation and this, in turn, correlates with the transcription of specific set of genes influencing the final biologic effect. Although during last years some efforts have been devoted to the characterization of AhR signaling pathways, various factors hamper the search for new AhR modulators endowed with immunomodulatory profile. Firstly, being modulated by a broad spectrum of synthetic and natural compounds possessing different scaffolds and physicochemical properties, AhR is defined as a promiscuous receptor. At the same time, a scarce knowledge about endogenous ligands and effects exerted exists, with the receptor being still orphan. Moreover, the high toxicity of most potent AhR ligands along with the lacking of a 3D structure of the Ligand Binding Domain (LBD) obstructs the characterization of molecular basis underlying AhR interaction. In this scenario, in the last 12 months I have successfully applied BioSolveIT package to identify new small molecule AhR modulators endowed with good affinity versus AhR using a ligand-based approach. Three non-toxic L-Tryptophan (L-Trp) metabolites, namely L-Kynurenine (L-Kyn, ki = 21.6*103 nM), ITE (ki = 3 nM) and FICZ (ki = 0.07 nM), have shown interesting pharmacologic properties being able to affect disease tolerance and to interfere with experimental autoimmune disorders. Considering the increasing interest for this target, these three ligands were chosen as references for the search of new AhR modulators. A Ligand Based Virtual Screening (LBVS) was carried out using FTrees and FlexS in an integrated fashion. Best selected virtual HITs were then purchased and tested through luciferase reporter assays and results were used to measure screening performance. The satisfactory obtained Hit-rate enabled the validation of LBVS protocol paving the way to a Hit-to-Lead optimization strategy. Hence, previously validated homology models were used to dock most promising compounds employing SeeSAR in an attempt to enhance compound potency through the design of analogues. Overall, the applied strategy has allowed the identification of two potent AhR modulators which are currently being tested in functional assays to prove their applicability to treat immune diseases.
For more information please visit the hall of fame.
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.
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.