title: Specific interactions and binding energies between thermolysin and potent inhibitors: molecular simulations based on ab initio molecular orbital method.
abstract: Biochemical functions of the metalloprotease thermolysin (TLN) are controlled by various inhibitors. In a recent study we identified 12 compounds as TLN inhibitors by virtual screening and in vitro competitive binding assays. However, the specific interactions between TLN and these inhibitors have not been clarified. We here investigate stable structures of the solvated TLN-inhibitor complexes by classical molecular mechanics simulations and elucidate the specific interactions between TLN and these inhibitors at an electronic level by using ab initio fragment molecular orbital (FMO) calculations. The calculated binding energies between TLN and the inhibitors are qualitatively consistent with the experimental results, and the FMO results elucidate important amino acid residues of TLN for inhibitor binding. Based on the calculated results, we propose a novel potent inhibitor having a large binding affinity to TLN.
authors: Department of Computer Science and Engineering, Toyohashi University of Technology, Tempaku-cho, Aichi, Japan.
authors: Tatsuya
authors: T
authors: Hirakawa
authors: Seiya
authors: S
authors: Fujita
authors: Tatsuya
authors: T
authors: Ohyama
authors: Kenichi
authors: K
authors: Dedachi
authors: Mahmud Tareq Hassan
authors: MT
authors: Khan
authors: Ingebrigt
authors: I
authors: Sylte
authors: Noriyuki
authors: N
authors: Kurita
mesh_terms: D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D007930:Leucine / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013820:Thermolysin / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D013820:Thermolysin; D007930:Leucine