title: Possible ligand release pathway of dipeptidyl peptidase IV investigated by molecular dynamics simulations.
abstract: Dipeptidyl peptidase IV (DPP4) is an important target for the treatment of Type II diabetes mellitus. The crystal structure of DPP4 demonstrates that there are two possible pathways to the active site, a side opening and a β propeller opening. However, it still lacks quantitative evidence to illustrate which pathway is more favorable for inhibitor to enter into or release from the active site. In this study, conventional and steered molecular dynamics simulations were performed to explore the details of inhibitor Q448 release from the active site of DPP4 via the two potential pathways. The comparisons of force and work together with potentials of mean force results suggested that the side opening might be more favorable for the inhibitor to pass through. Moreover, Glu205-Glu206 and Phe357 were recognized as two "key residues" in the active site for inhibitor binding. Accordingly, suggestions for further inhibitor design were provided.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
authors.forename: Cui
authors.initials: C
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
authors.forename: Chunhua
authors.initials: C
authors.lastname: Lu
authors.forename: Guixia
authors.initials: G
authors.lastname: Liu
authors.forename: Yun
authors.initials: Y
authors.lastname: Tang
mesh_terms: D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology*; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D008024:Ligands; D018819:Dipeptidyl Peptidase 4