Osteoarthritis (OA) is a leading cause of age-related disability worldwide, mainly affecting women over fifty. Current treatments target symptoms, not the cause. Matrix Metalloproteinase-13 (MMP-13), deregulated in OA, is a promising therapeutic target. THRIVE proposes using Targeted Protein Degradation (TPD) to direct MMP-13 to lysosomal degradation, offering a novel OA treatment.
THRIVE designs and evaluates Lysosome Targeting Chimeras (LYTACs) for MMP-13 using advanced computational tools, including high-throughput virtual screening (HTVS), molecular dynamics (MD), Free Energy Perturbation (FEP), and machine learning (ML) for permeability predictions. It also predicts physicochemical properties and dynamic behavior to shortlist candidates for experimental synthesis. With no FDA/EMA-approved MMP-13 inhibitors and the gender disparity in OA, THRIVE addresses a critical societal need.
Karuna Anna intends to achieve the following milestones:
- Design of MMP ligand- Rational design and computational evaluation of MMP-13 selective ligands using HTVS, selecting ~10 candidates
- Design of CI-MPR ligand- Selection of 10 LYTAC scaffold candidates using HTVS against CI-M6PR and filtering based on synthetic accessibility
- Linker design using MD simulations, click chemistry feasibility using QM calculations and bioavailiabilty prediction using HobPre model .