Using induced-fit docking plus FEP to design away from CYP, hERG and PXR
- Anti-targets such as CYP3A4, CYP2D6, hERG and PXR have large, flexible sites that make structure-based design difficult.
- The workflow pairs induced-fit docking with free energy perturbation, enforcing a consensus binding mode across a congeneric series to sample receptor conformations efficiently.
- It was tested on public retrospective datasets and applied prospectively in active drug discovery programs.
💡 Points
Most teams treat hERG and CYP as a post-hoc assay problem; getting usable FEP on these promiscuous pockets would move liability into the design cycle. The consensus-binding-mode restriction is the clever bit, but it also limits you to congeneric series. Prospective hit rates on novel scaffolds will show whether this holds beyond the series it was tuned on.