<b>RORγt: A Drug Target in Organ Transplantation — Identification of Novel Modulators of RORγt by Rational Drug Design and Molecular Docking</b>

This poster presented an integrated computational and experimental drug discovery study aimed at identifying novel small-molecule modulators of the retinoic acid receptor-related orphan receptor gamma t (RORγt), a transcription factor that orchestrates T helper 17 (Th17) cell differentiation and cytokine secretion. Dysregulated Th17 responses have been strongly implicated in antibody-mediated rejection (AMR) and chronic allograft dysfunction through the formation of tertiary lymphoid tissue and the secretion of pro-inflammatory cytokines such as IL-17A, IL-21, and IL-22. Targeting RORγt therefore represents a promising immunomodulatory strategy in transplantation. The project implemented a rational drug design workflow combining multiple stages of in-silico and in-vitro screening. Over 90 million compounds from the PubChem chemical library and 152 RORγt bioassays were analyzed to identify potential RORγt inverse agonists. Computational steps included 2D/3D fingerprint similarity screening, molecular docking, property calculation, and virtual ADMET filtering to prioritize candidates with optimal predicted pharmacokinetics and safety profiles. Two compounds, TF-S1 and TF-S2, emerged as promising hit molecules with strong binding affinity for the RORγt ligand-binding domain and favorable drug-likeness characteristics. Their biological activity was validated using in-vitro Th17 polarization assays based on peripheral blood mononuclear cells (PBMCs) from highly sensitized (HSP) and nonsensitized (NSP) transplant patients, as well as healthy volunteers (HV). The cultures were stimulated with IL-1β, IL-6, IL-23, and TGF-β over 16 days, followed by intracellular cytokine staining and multicolor flow cytometry to quantify CD4⁺IL-17A⁺, CD4⁺IL-21⁺, and CD4⁺IL-22⁺ populations. Treatment with TF-S1 and TF-S2 significantly attenuated Th17 polarization and cytokine expression, with inhibitory effects comparable to those observed with cyclosporine A (CsA) and dexamethasone (DEX). The response was dose-dependent and consistent across patient groups, supporting the hypothesis that these compounds act as functional RORγt inverse agonists. Statistical analysis using two-way ANOVA with Tukey’s or paired t-tests confirmed significance (p < 0.05). The findings demonstrated that selective inhibition of RORγt can effectively modulate Th17-mediated immune activation, offering a potential therapeutic approach for reducing allosensitization, AMR, and chronic graft inflammation. Beyond its immediate biological results, the poster emphasized the power of integrating computational chemistry, virtual pharmacology, and cellular immunology to accelerate small-molecule discovery in transplantation research.Title: RORγt: A Drug Target in Organ Transplantation — Identification of Novel Modulators of RORγt by Rational DrugPoster presented on: 24 October 2018Conference: IVth International Drug Discovery and Development Forum 2018Location: Montreal, QC, CanadaAuthors: Ahmed Fouda, Sarita Negi, Steven Paraskevas, Jean TchervenkovAffiliation: Division of Surgical and Interventional Sciences (formely Department of Experimental Surgery), Department of Surgery, McGill University, Montreal, QC, Canada📚 Full Citation Fouda, A.; Negi, S.; Paraskevas, S.; Tchervenkov, J. RORγt: A Drug Target in Organ Transplantation — Identification of Novel Modulators of RORγt by Rational Drug Design and Molecular Docking. Poster presented at the IVth International Drug Discovery and Development Forum 2018, Montreal, QC, Canada, October 22–24, 2018. McGill University. DOI: 10.6084/m9.figshare.30415822. © 2018, Ahmed Fouda.

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