title: Molecular modeling study for inhibition mechanism of human chymase and its application in inhibitor design.
abstract: Human chymase catalyzes the hydrolysis of peptide bonds. Three chymase inhibitors with very similar chemical structures but highly different inhibitory profiles towards the hydrolase function of chymase were selected with the aim of elucidating the origin of disparities in their biological activities. As a substrate (angiotensin-I) bound crystal structure is not available, molecular docking was performed to dock the substrate into the active site. Molecular dynamics simulations of chymase complexes with inhibitors and substrate were performed to calculate the binding orientation of inhibitors and substrate as well as to characterize conformational changes in the active site. The results elucidate details of the 3D chymase structure as well as the importance of K40 in hydrolase function. Binding mode analysis showed that substitution of a heavier Cl atom at the phenyl ring of most active inhibitor produced a great deal of variation in its orientation causing the phosphinate group to interact strongly with residue K40. Dynamics simulations revealed the conformational variation in region of V36-F41 upon substrate and inhibitor binding induced a shift in the location of K40 thus changing its interactions with them. Chymase complexes with the most active compound and substrate were used for development of a hybrid pharmacophore model which was applied in databases screening. Finally, hits which bound well at the active site, exhibited key interactions and favorable electronic properties were identified as possible inhibitors for chymase. This study not only elucidates inhibitory mechanism of chymase inhibitors but also provides key structural insights which will aid in the rational design of novel potent inhibitors of the enzyme. In general, the strategy applied in the current study could be a promising computational approach and may be generally applicable to drug design for other enzymes.
authors: Division of Applied Life Science, Systems and Synthetic Agrobiotech Center (SSAC), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), Jinju, Republic of Korea.
authors: Mahreen
authors: M
authors: Arooj
authors: Songmi
authors: S
authors: Kim
authors: Sugunadevi
authors: S
authors: Sakkiah
authors: Guang Ping
authors: GP
authors: Cao
authors: Yuno
authors: Y
authors: Lee
authors: Keun Woo
authors: KW
authors: Lee
mesh_terms: D053818:Chymases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011487:Protein Conformation
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D053818:Chymases
references: J Comput Chem. 2005 Dec;26(16):1701-18
references: 16211538
references: J Chem Theory Comput. 2008 Mar;4(3):435-47
references: 26620784
references: Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):6738-42
references: 7624313
references: Eur Heart J. 2010 Mar;31(6):642-8
references: 20176800
references: J Comput Chem. 2007 Apr 30;28(6):1145-52
references: 17274016
references: Bioorg Med Chem Lett. 2001 Jul 9;11(13):1695-7
references: 11425540
references: Genet Med. 2008 Aug;10(8):593-8
references: 18641516
references: Lasers Med Sci. 2009 Mar;24(2):223-9
references: 18408985
references: Biochem Pharmacol. 2010 Oct 1;80(7):1033-41
references: 20599788
references: Nat Struct Mol Biol. 2006 Sep;13(9):839-48
references: 16936729
references: Biochim Biophys Acta. 2002 Apr 29;1596(2):346-56
references: 12007614
references: J Immunol. 2006 Dec 15;177(12):8315-9
references: 17142727
references: Basic Res Cardiol. 2010 Jul;105(4):513-22
references: 20340028
references: Blood. 2010 Jun 17;115(24):4981-90
references: 20233968
references: Biopolymers. 1988 Nov;27(11):1795-815
references: 3233332
references: Bioorg Med Chem Lett. 2000 Feb 7;10(3):199-201
references: 10698435
references: J Med Chem. 2007 Apr 19;50(8):1727-30
references: 17361995
references: J Biol Chem. 2005 May 6;280(18):18001-7
references: 15741158
references: Biochim Biophys Acta. 2000 Jul 14;1480(1-2):245-57
references: 10899625
references: Int J Mol Sci. 2011;12(12):9236-64
references: 22272131
references: Bioorg Med Chem Lett. 2003 Nov 17;13(22):4085-8
references: 14592513
references: Am J Physiol Renal Physiol. 2010 Jan;298(1):F35-6
references: 19923404
references: Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26
references: 11259830
references: Bioorg Med Chem Lett. 2000 Nov 6;10(21):2397-401
references: 11078187
references: Biochem Biophys Res Commun. 2009 Dec 18;390(3):608-12
references: 19819222
references: J Med Chem. 2007 Feb 22;50(4):726-41
references: 17300160
references: Biochemistry. 1997 Nov 25;36(47):14318-24
references: 9400368
references: Chem Biol Drug Des. 2012 Dec;80(6):862-75
references: 22834787
references: Biopolymers. 1994 Jan;34(1):143-53
references: 8110966
references: J Am Soc Nephrol. 2003 Jul;14(7):1738-47
references: 12819233
references: Eur Heart J. 2007 Mar;28(6):711-8
references: 17339265
references: Biochem Biophys Res Commun. 1998 Jan 6;242(1):158-63
references: 9439628
references: Bioorg Med Chem Lett. 2003 Jan 6;13(1):25-9
references: 12467610