| By name, structure-based drug design relies on having the structure of the protein and ligand of interest as a starting point. Because structural determination is difficult, there are many proteins of clinical interest whose structures have not yet been determined. In some cases, protein structures may be ambiguously known. Three cases are set forth, each with protein and ligand structures unresolved, to varying degrees. New approaches are devised to allow for a better understanding of the likely structures of the protein-ligand complexes.; The Relaxed-Complex method is introduced, and is used to elucidate the binding mode of the 5CITEP inhibitor for HIV integrase. Further work identifies a novel trench near the active site of integrase that should be considered for future anti-HIV integrase drug design.; The Exhaustive Restrained Minimization Algorithm (ERMA) was devised to discover the likely binding mode of a known MMP-3 inhibitor for the metalloenzyme, a complex whose structure had been unknown previously. The computationally determined complex conformation of MMP-3 with its inhibitor was used as a starting point for de novo drug design for MMP-3 inhibitors, with mildly successful initial results.; I have shown new ways of accounting for protein flexibility with molecular docking, and have introduce two new methods, the Relaxed-Complex and Exhaustive Restrained Minimization Algorithm, that allow for structure-based drug design in cases where the structure of the protein-ligand complex is not confidently known. These approaches should be used for further work, along with increased ways of accounting for protein flexibility in structure-based drug design. |
