Analysis of binding conformations of drugs to human serum albumin (site I and site II) by NMR measurements and computational calculations
Grant-in-Aid for Scientific Research (C)
|Allocation Type||Single-year Grants|
|Research Institution||Kitasato University|
HIRONO Shuichi School of Pharm. Sci. Kitasato Univ. Professor, 薬学部, 教授 (30146328)
GOUDA Hiroaki School of Pharm. Sci. Kitasato Univ. Assistant Professor, 薬学部, 講師 (60276160)
YAMAOTSU Noriyuki School of Pharm. Sci. Kitasato Univ. Assistant, 薬学部, 助手 (60230322)
MATSUSHITA Yasuo School of Pharm. Sci. Kitasato Univ. Assistant Professor, 薬学部, 講師 (40050653)
NAKAGOME Izumi School of Pharm. Sci. Kitasato Univ. Assistant, 薬学部, 助手 (30237242)
|Project Period (FY)
1998 – 1999
Completed(Fiscal Year 1999)
|Budget Amount *help
¥1,900,000 (Direct Cost : ¥1,900,000)
Fiscal Year 1999 : ¥500,000 (Direct Cost : ¥500,000)
Fiscal Year 1998 : ¥1,400,000 (Direct Cost : ¥1,400,000)
|Keywords||Molecular Dynamics / CAMDAS / SUPERPOSE / TRNOE / HAS / Protein Binding / Site I / Site II / 分子重ね合わせ法 / NMR|
(1) The binding conformations of drugs to site I and site II of HAS has been investigated by CAMDAS, SUPERPOSE and TRNOE experiments. We have combined distance information obtained from CAMDAS and TRNOE to perform an extraction of a "binding conformer" for drugs binding to the HAS (site I and site II ).
(2) Site I binding drugs
For BMT, one selected conformer (BMT354) was obtained. The basic binding conformer structure of BMT354 was taken as a "template" to choose binding conformers for FUCI and IM. Consequently, we could efficiently select one binding conformer for FUCI and IM.
(3) Site II binding drugs
For tolmetin (TLM), only one conformer (TLM 53) among conformers generated by CAMDAS satisfied the distance restraint conditions obtained from NOESY. The structure of the TLM (conf53) was taken as a "template" to choose binding conformers for other drugs by molecular overlay. We could efficiently select one binding conformer for ETH-A, R-IB, S-IB, R-KP and S-KP.
(4) Then, we constructed the complex structure of drugs (BMT354, TLM53) and HAS based on the crystal structure of HAS using Flexi Dock program implemented in SYBYL (Tripos).
This method of combining MD calculation, SUPERPOSE and TRNOE measurements suggested to an extremely effective method for obtaining steric conformation for drugs bound to HAS.
Binding conformer of the drugs in the binding site (site I and site II ) of HAS was used to probe the drug-HAS complementary interactions.
Research Products (11results)