2000 Fiscal Year Annual Research Report

疎水的表面積による薬物・受容体の構造と結合定数の予測

Research Project

Project/Area Number	11672153
Research Institution	KYOTO PHARMACEUTICAL UNIVERSITY
Principal Investigator	舟崎紀昭京都薬科大学, 薬学部, 教授 (20065915)
Co-Investigator(Kenkyū-buntansha)	石川誠司京都薬科大学, 薬学部, 助手秦さかえ京都薬科大学, 薬学部, 助手 (20322563)
Keywords	分子表面積 / 結合定数 / 疎水性 / 複合体 / 薬物受容体 / 分子構造
Research Abstract	1.疎水的分子表面積の減少を計算するためのソフトを開発し、ホスト・ゲスト系のモデルとしてシクロデキストリンの包接系に適用した。ホスト分子の空洞の大きさが異なるシクロデキストリンと種々の化学構造を持つゲスト分子の系について、疎水的分子表面積の減少が最大になる構造が安定で、その疎水的分子表面積の減少が結合定数と一義的な直線関係を示すことを見出した。 2.水中における抗潰瘍薬である臭化オキシフェノニウムの溶液構造を核磁気共鳴法で決定し、分子力学から予測した構造は水和エネルギーを充分考慮していないので、完全には一致しないが、親水性表面積が大きく、疎水性表面積が小さい構造はよく一致することを示した。 3.疎水的分子表面積の減少から予測されたシクロデキストリン包接複合体の溶液構造は結晶構造とわずかに異なり、核磁気共鳴により決定した溶液構造にほぼ一致すること、また、疎水的分子表面積の減少から予測した結合定数もほぼ実測値に一致することを見出した。さらに、2種類の複合体が共存する特異な系を見出し、その構造を詳細に決定し、分子表面積から存在比を推定できることを示した。 4.シクロデキストリンによる薬の苦みと溶血性の抑制機構は、シクロデキストリンが遊離の薬分子の濃度を低下させるためであることを証明した。表面張力値と起電力の実測値、さらには、コンピュータで理論的に遊離の薬分子の濃度を推定できるので、苦み実験や溶血実験をすることなく、添加すべきシクロデキストリンの種類と濃度を決定できることが可能になった。 5.薬物と受容体、酵素と基質、酵素と阻害剤などの複合体の構造と結合定数をコンピュータで予測することは、最小の費用で迅速に新しい薬をデザインしたり、シクロデキストリンなどの添加による薬の製剤化したりする薬学の多くの分野において緊急の課題になってきている。以上の研究はこのような社会の要請に応えるものである。

Research Products
(18 results)

All Other

All Publications (18 results)

[Publications] N.Funasaki,R.Kawaguchi,S.Hada,S.Neya: "Ultraviolet spectroscopic estimation of microenvironments and bitter tastes of oxyphenonium bromide in cyclodextrin solutions"J.Pharm.Sci.. 88. 759-762 (1999)
[Publications] N.Funasaki,S.Hada,S.Neya: "Self-association patterns of sodium taurocholate and taurodeoxycholate as studied by frontal derivative chromatography"J.Phys.Chem.B,. 103. 169-172 (1999)
[Publications] N.Funasaki,M.Ohigashi,S.Hada,S.Neya: "Quantitative prediction of the suppression of drug-induced hemolysis by cyclodextrins from surface tension data"Langmuir. 15. 594-599 (1999)
[Publications] S.Ishikawa,S.Hada,S.Neya,N.Funasaki: "Calculations of molecular surface area changes with docking of host and guest and applications to cyclodextrin inclusion"J.Phys.Chem.B. 103. 1208-1215 (1999)
[Publications] S.Hada,S.Ishikawa,S.Neya,N.Funasaki: "Dimerization and α-cyclodextrin inclusion of propantheline bromide as studied by NMR and molecular modeling"J.Phys.Chem.B. 103. 2579-2584 (1999)
[Publications] N.Funasaki,R.Kawaguchi,S.Ishikawa,S.Hada,S.Neya,T.Katsu: "Quantitative estimation of the bitter taste intensity of oxyphenonium bromide reduced by cyclodextrins from electromotive force measurements"Anal.Chem.. 71. 1733-1736 (1999)
[Publications] N.Funasaki,M.Ohigashi,S.Hada,S.Neya: "Surface tensiometric study of multiple complexation and hemolysis by mixed surfactants and cyclodextrins"Langmuir. 16. 383-388 (2000)
[Publications] N.Funasaki,S.Neya: "Multiple complexation of didecyldimethylammonium bromide and cyclodextrins deduced from electromotive force measurements"Langmuir. 16. 5343-5346 (2000)
[Publications] N.Funasaki,S.Ishikawa,S.Neya: "Stepwise self-association of penicillin V as studied by frontal derivative chromatography."Langmuir. 16. 5584-5587 (2000)
[Publications] N.Funasaki,M.Nomura,S.Ishikawa,S.Neya: "Hydrophobic self-association of sodium taurochenodeoxycholate and tauroursodeoxycholate."J.Phys.Chem.B. 104. 7745-7751 (2000)
[Publications] N.Funasaki,H.Yamaguchi,S.Ishikawa,S.Neya: "Hydration effect on molecular conformation of oxyphenonium bromide "J.Phys.Chem.B. 104. 10412-10418 (2000)
[Publications] N.Funasaki,M.Nomura,H.Yamaguchi,S.Ishikawa,S.Neya: "References for NMR chemical shift measurements in cyclodextrin solutions "Bull.Chem.Soc.Jpn.. 73. 2727-2728 (2000)
[Publications] N.Funasaki,H.Yamaguchi,S.Hada,S.Neya: "Complex formation of benzenesulfonate and α-cyclodextrin estimated from NMR and hydrophobic molecular surface areas"J.Phys.Chem.B. 105. 760-765 (2001)
[Publications] N.Funasaki,S.Ishikawa,S.Neya: "Stoichiometric and microenviromental effects on hydrolysis of propantheline and oxyphenonium bromides in cyclodextrin solutions"J.Pharm.Sci.. 90(In press). (2001)
[Publications] N.Funasaki,T.Okuda,S.Neya: "Mechanisms and surface chemical prediction of imipramine-induced hemolysis suppressed by modified cyclodextrins"J.Pharm.Sci.. 90(In press). (2001)
[Publications] 舟崎紀昭ほか: "物性物理化学"南江堂. 256 (2000)
[Publications] N.Funasaki et al: "Organized assemblies in chemical analysis. Bile acid/salt surfactant systems. Vol 2"Jai Press. 346 (2000)
[Publications] S.Ishikawa,S.Neya,N.Funasaki: "Studies in surface science and catalysis"Elsevier Science (In press). (2001)

2000 Fiscal Year Annual Research Report

疎水的表面積による薬物・受容体の構造と結合定数の予測

Principal Investigator

舟崎 紀昭 京都薬科大学, 薬学部, 教授 (20065915)

Research Products

[Publications] N.Funasaki,R.Kawaguchi,S.Hada,S.Neya: "Ultraviolet spectroscopic estimation of microenvironments and bitter tastes of oxyphenonium bromide in cyclodextrin solutions"J.Pharm.Sci.. 88. 759-762 (1999)

[Publications] N.Funasaki,S.Hada,S.Neya: "Self-association patterns of sodium taurocholate and taurodeoxycholate as studied by frontal derivative chromatography"J.Phys.Chem.B,. 103. 169-172 (1999)

[Publications] N.Funasaki,M.Ohigashi,S.Hada,S.Neya: "Quantitative prediction of the suppression of drug-induced hemolysis by cyclodextrins from surface tension data"Langmuir. 15. 594-599 (1999)

[Publications] S.Ishikawa,S.Hada,S.Neya,N.Funasaki: "Calculations of molecular surface area changes with docking of host and guest and applications to cyclodextrin inclusion"J.Phys.Chem.B. 103. 1208-1215 (1999)

[Publications] S.Hada,S.Ishikawa,S.Neya,N.Funasaki: "Dimerization and α-cyclodextrin inclusion of propantheline bromide as studied by NMR and molecular modeling"J.Phys.Chem.B. 103. 2579-2584 (1999)

[Publications] N.Funasaki,R.Kawaguchi,S.Ishikawa,S.Hada,S.Neya,T.Katsu: "Quantitative estimation of the bitter taste intensity of oxyphenonium bromide reduced by cyclodextrins from electromotive force measurements"Anal.Chem.. 71. 1733-1736 (1999)

[Publications] N.Funasaki,M.Ohigashi,S.Hada,S.Neya: "Surface tensiometric study of multiple complexation and hemolysis by mixed surfactants and cyclodextrins"Langmuir. 16. 383-388 (2000)

[Publications] N.Funasaki,S.Neya: "Multiple complexation of didecyldimethylammonium bromide and cyclodextrins deduced from electromotive force measurements"Langmuir. 16. 5343-5346 (2000)

[Publications] N.Funasaki,S.Ishikawa,S.Neya: "Stepwise self-association of penicillin V as studied by frontal derivative chromatography."Langmuir. 16. 5584-5587 (2000)

[Publications] N.Funasaki,M.Nomura,S.Ishikawa,S.Neya: "Hydrophobic self-association of sodium taurochenodeoxycholate and tauroursodeoxycholate."J.Phys.Chem.B. 104. 7745-7751 (2000)

[Publications] N.Funasaki,H.Yamaguchi,S.Ishikawa,S.Neya: "Hydration effect on molecular conformation of oxyphenonium bromide "J.Phys.Chem.B. 104. 10412-10418 (2000)

[Publications] N.Funasaki,M.Nomura,H.Yamaguchi,S.Ishikawa,S.Neya: "References for NMR chemical shift measurements in cyclodextrin solutions "Bull.Chem.Soc.Jpn.. 73. 2727-2728 (2000)

[Publications] N.Funasaki,H.Yamaguchi,S.Hada,S.Neya: "Complex formation of benzenesulfonate and α-cyclodextrin estimated from NMR and hydrophobic molecular surface areas"J.Phys.Chem.B. 105. 760-765 (2001)

[Publications] N.Funasaki,S.Ishikawa,S.Neya: "Stoichiometric and microenviromental effects on hydrolysis of propantheline and oxyphenonium bromides in cyclodextrin solutions"J.Pharm.Sci.. 90(In press). (2001)

[Publications] N.Funasaki,T.Okuda,S.Neya: "Mechanisms and surface chemical prediction of imipramine-induced hemolysis suppressed by modified cyclodextrins"J.Pharm.Sci.. 90(In press). (2001)

[Publications] 舟崎紀昭 ほか: "物性物理化学"南江堂. 256 (2000)

[Publications] N.Funasaki et al: "Organized assemblies in chemical analysis. Bile acid/salt surfactant systems. Vol 2"Jai Press. 346 (2000)

[Publications] S.Ishikawa,S.Neya,N.Funasaki: "Studies in surface science and catalysis"Elsevier Science (In press). (2001)

舟崎紀昭京都薬科大学, 薬学部, 教授 (20065915)

[Publications] 舟崎紀昭ほか: "物性物理化学"南江堂. 256 (2000)