Bound Ligand Conformer Revealed by Flexible Structure Alignment in Absence of Crystal Structures: Indirect Drug...

In the absence of structural knowledge on the target protein, the bound ligand conformer (BLC) can be constructed approximately by an indirect drug-design approach that uses a set of ligands binding to the same target. Once the bound ligand conformer (BLC) is known, different strategies of drug design can be pursued. The indirect drug-design approach of the present study is based on the assumption that a set of ligands with chemically different architecture binding to the same target protein carry hidden information of their corresponding true BLCs. It is shown how this information can be extracted by pairwise flexible structure alignment (FSA) using molecular dynamics (MD) simulations with attractive intermolecular interactions that derive from the molecular similarity of the ligands and allow the ligands to adopt the same space. The FSA approach is performed with a newly designed module overlap in the experimental CHARMM-29a1, which soon will become publicly available. Combining the conformations obtained from FSA of different ligand pairs yields consensus ligand conformers (CLCs) that should be similar to the BLCs. This procedure was validated on HIV-1 protease (HIV-P), where at present 44 crystal structures with bound ligands of sufficiently diverse chemical composition are available. The FSA approach identifies four different clusters of HIV-P BLCs. These clusters are consistent with the H-bond patterns of the ligands bound to HIV-P in the crystal structures exhibiting four different binding modes. The cluster-specific CLCs are indeed very similar (rmsd ≈ 2 Å) to the corresponding BLCs from the crystal structure, demonstrating the feasibility of the present approach.