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03월 02일 17시 이후 : 초록수정 불가능, 일정확인 및 검색만 가능
제109회 대한화학회 학술발표회, 총회 및 기기전시회 안내
Protein-ligand docking of known 5-lipoxygenase inhibitors
2012년 2월 6일 16시 43분 13초
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4월 25일 (수요일) 18:00~21:00
한국파스퇴르연구소 의약화학그룹1, Korea
한국파스퇴르연구소 late discovery program(LDP), Korea
5-lipoxygenase (5-LO) is an important factor in immune and inflammatory responses, and allergic and inflammatory disorders and also possibly atherosclerosis can be intervened by inhibition of 5-LO. Despite many years of discovery for 5-LO inhibitors, only one clinically approved 5-LO inhibitor is available which is Zileuton. However, Zileuton has shown a variety of adverse effects related to hepatic toxicities. With recent discovery of human 5-LO x-ray crystal structure (3O8Y.pdb), we have applied in silico protein-ligand docking method to analyze how known iron-chelator, redox and non-redox 5-LO inhibitors would bind in the active site. CDOCKER program in Discovery Studio suite (Accelrys, Inc.) was used for docking. Binding site for docking included all the residues coordinating the ferric iron (H367, H372, H550, N554, I673) and those of the active site. Two iron chelator 5-LO inhibitors, Zileuton and CGS-23885 were docked into the active site. The hydroxyurea group of both compounds docked near the ferric atom suggesting iron chelation. In addition, this group of Zileuton, and the oxygen atom in the chromene group of CGS-23885 formed hydrogen bonds (H-bonds) with H367. The aromatic rings of CGS-23885 were well positioned and surrounded by active site hydrophobic residues. This may be the reason for lower docked energy than Zileuton. A redox inhibitor, R-68151, has a phenolic group in the structure. The hydroxyl moiety of the phenolic group formed H-bond with I673. The long elongated shape with four rings of R-68151 filled up the tubular shape active site by having hydrophobic and van der Waals interactions with the active site residues. As a comparison, a non-redox inhibitor, CJ-13610, was also docked into the active site of 5-LO. It didn’t form any H-bond with either iron coordinating or active site residues. In conclusion, compounds forming H-bonds with at least one of the five iron coordinating residues had redox or iron chelating properties. Also, docking results showed how the chemical functional groups interact with the active site residues. This structure-activity relationship information from docking results could be the basis for developing 5-LO inhibitors with improved efficacy and toxicity profiles.
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