We have designed a structure-based, BioSolveIT-driven project against three essential, complementary targets — BamA, Class B MBLs (NDM/VIM/IMP) and LpxC — using the CoLibri natural product Chemical Space we had earlier built from five different sources. The work proceeds in three phases. Phase 1: curate 34 crystal structures, build and validate A. baumannii BamA and LpxC models, and intersect Fpocket, CASTp, DoGSiteScorer, P2Rank and SeeSAR into a consensus druggability matrix defining primary (Tier 1), allosteric, and cryptic pockets. Phase 2: template-guided Chemical Space Docking at each Tier 1 site, then FlexX redocking, FTrees, SpaceLight, a natural-product-aware SpaceMACS/RDKit toxicity gate, Butina clustering and FastGrow growing. Phase 3: MD, MM-PBSA and FEP validation, resistance and cross-species mutagenesis, and fixed-weight prioritisation into a tiered, toxicity-annotated lead set with routes. The project will deliver outcomes with synergistic resistance-beating potential.
Ashok intends to achieve the following milestones:
- Prepare 34 structures plus Ab cofolded / homology models; five-tool consensus pocket and druggability atlas
- FlexX docking of natural product space vs BamA, MBL, LpxC; filter, cluster and FastGrow-optimise hit series
- MD, FEP and resistance profiling; ranked four-tier lead set with routes and toxicity annotation