Diprolyl nitriles as potent dipeptidyl peptidase IV inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 15, Issue 18, 2005, Pages 3992-3995

  Zhao, Guohua ^a   Taunk, Prakash C ^a   Magnin, David R ^a   Simpkins, Ligaya M ^a   Robl, Jeffrey A ^a   Wang, Aiying ^a   Robertson, James G ^a   Marcinkeviciene, Jovita ^a   Sitkoff, Doree F ^a   Parker, Rex A ^a   Kirby, Mark S ^a   Hamann, Lawrence G ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

Dipeptidyl peptidase IV; Diprolyl nitriles

Indexed keywords

AMINO ACID DERIVATIVE; ANTIDIABETIC AGENT; DIPEPTIDYL PEPTIDASE IV; DIPEPTIDYL PEPTIDASE IV INHIBITOR; GLUCOSE; MEMBRANE ENZYME; NITRILE; PEPTIDE HORMONE;

AMINO ACID SYNTHESIS; AMINO TERMINAL SEQUENCE; ARTICLE; DRUG IDENTIFICATION; DRUG INHIBITION; DRUG MECHANISM; DRUG POTENCY; DRUG SYNTHESIS; ENZYME ACTIVITY; GLUCOSE BLOOD LEVEL; GLUCOSE HOMEOSTASIS; MEASUREMENT; NON INSULIN DEPENDENT DIABETES MELLITUS; PROTEIN DEGRADATION; REGULATORY MECHANISM; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION;

ANTIGENS, CD26; BINDING SITES; CYCLIZATION; MODELS, MOLECULAR; MOLECULAR STRUCTURE; NITRILES; PROTEASE INHIBITORS; PROTEIN STRUCTURE, TERTIARY;

EID: 23644440644     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2005.06.043     Document Type: Article

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20. The binding model shown was obtained by sampling conformations of l-prolyl-proline in the gas phase using the Monte Carlo tool in Macromodel v. 8.1031 (Schrodinger, Inc.) and minimizing representative structures in AMPAC v. 6.55 (Semichem, Inc.) with the SAM1 Hamiltonian. Two low energy conformations were obtained, distinguished by rotation of the P2 pyrrolidine. The structures were overlaid on the bound ligand of pdb structure 1N1M (Ref. 15) based on the common acylpyrrolidine substructure; one conformation was discarded due to van der Waals clashes with the protein in the S2 pocket; the remaining conformation (depicted in Fig. 3) places the charged amino group close to that of the 1N1M ligand. The figure was created with Maestro v. 7.0.110 (Schrodinger, Inc.) using a surface probe radius of 1.8 Å. The protein surface is colored green; carbons in the ligand are colored magenta, oxygens are red, and nitrogens are blue. The hydrogens on C4 are shown explicitly in white; all other hydrogens are hidden.
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