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Characterization of crystal water molecules in a high-affinity inhibitor and hematopoietic prostaglandin D synthase complex by interaction energy studies

DOI: 10.1016/j.bmc.2018.08.014 DOI Help

Authors: Daisuke Takaya (RIKEN Center for Biosystems Dynamics Research) , Koji Inaka (MARUWA Foods and Biosciences, Inc) , Akifumi Omura (Asahi Kasei Pharma Corporation) , Kenji Takenuki (Asahi Kasei Pharma Corporation) , Masashi Kawanishi (Asahi Kasei Pharma Corporation) , Yukako Yabuki (RIKEN Center for Biosystems Dynamics Research) , Yukari Nakagawa (RIKEN Center for Biosystems Dynamics Research) , Keiko Tsuganezawa (RIKEN Center for Biosystems Dynamics Research) , Naoko Ogawa (RIKEN Center for Biosystems Dynamics Research) , Chiduru Watanabe (RIKEN Center for Biosystems Dynamics Research) , Teruki Honma (RIKEN Center for Biosystems Dynamics Research) , Kosuke Aritake (University of Tsukuba) , Yoshihiro Urade (University of Tsukuba) , Mikako Shirouzu (RIKEN Center for Biosystems Dynamics Research) , Akiko Tanaka (RIKEN Center for Biosystems Dynamics Research)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry

State: Published (Approved)
Published: August 2018

Abstract: Hematopoietic prostaglandin D synthase (H-PGDS) is one of the two enzymes that catalyze prostaglandin D2 synthesis and a potential therapeutic target of allergic and inflammatory responses. To reveal key molecular interactions between a high-affinity ligand and H-PGDS, we designed and synthesized a potent new inhibitor (KD: 0.14 nM), determined the crystal structure in complex with human H-PGDS, and quantitatively analyzed the ligand–protein interactions by the fragment molecular orbital calculation method. In the cavity, 10 water molecules were identified, and the interaction energy calculation indicated their stable binding to the surface amino acids in the cavity. Among them, 6 water molecules locating from the deep inner cavity to the peripheral part of the cavity contributed directly to the ligand binding by forming hydrogen bonding interactions. Arg12, Gly13, Gln36, Asp96, Trp104, Lys112 and an essential co-factor glutathione also had strong interactions with the ligand. A strong repulsive interaction between Leu199 and the ligand was canceled out by forming a hydrogen bonding network with the adjacent conserved water molecule. Our quantitative studies including crystal water molecules explained that compounds with an elongated backbone structure to fit from the deep inner cavity to the peripheral part of the cavity would have strong affinity to human H-PGDS.

Journal Keywords: Hematopoietic prostaglandin D synthase; Crystal water molecule; Interaction energy; Fragment molecular orbital method; Crystal structure analysis; Drug design

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-Macromolecular Crystallography