合同分 科 会

選 出2010 年度 合同分科会 より

特別講演

創薬における Exa computing への期待

大正製薬株式会社
北村 一泰ഃ⮎䈮䈍䈔䉎㪜㫏㪸㩷㪺㫆㫄㫇㫌㫋㫀㫅㪾䈻䈱ᦼᓙ1䋩ක⮎䈱ᓎ⋡䉕৻⸒䈪⴫⃻䈜䉏䈳
2䋩ක⮎R&D䊒䊨䉶䉴䈱⚫੺䋨᭎ⷐ䋩
3䋩ഃ⮎䈮䈍䈔䉎ಽሶ⸘▚䋨⃻⁁䋩
4䋩ഃ⮎䈮䈍䈔䉎Exa computing䈻䈱ᦼᓙ“ක⮎㵱䈱ᓎ⋡䉕৻⸒䈪⴫⃻䈜䉏䈳!!

ർ᧛ ৻ᵏᄢᱜ⵾⮎䋨ᩣ䋩䉰䉟䉣䊮䊁䉞䊐䉞䉾䉪䊶䉲䉴䊁䊛⎇ⓥળ

10/21/2010 ␹ᚭ21䋩㵱ක⮎㵰䈱ᓎ⋡䉕৻⸒䈪⴫⃻䈜䉏䈳∔㩷ᖚ䇭⛔วᄬ⺞∝䈉䈧∛ක⮎ຠ䈱ක≮⽸₂଀*৻㩷⥸㩷ฬ䉪䊨䊦䊒䊨䊙䉳䊮䋨㪈㪐㪌㪉䋩䉮䊮䊃䊚䊮㪆䉡䉟䊮䉺䊚䊮䋨䊄䊷䊌䊚䊮㪛㪉ᜟ᛫䋩㩷㪈㪐㪌㪇㩷䊨䊷䊮䊶䊒䊷䊤䊮䋨⃻䉰䊉䊐䉞䊶䉝䊔䊮䊁䉞䉴䋩䊌䊨䉨䉶䉼䊮㩷䋨㪈㪐㪐㪈䋩ਇ቟㓚ኂ䊔䊮䊤䊐䉜䉨䉲㩷䋨㪈㪐㪐㪋䋩ᓴⅣེ♽∔ᖚᶖൻᕈẩ≌䉲䊜䉼䉳䊮㩷䋨㪈㪐㪎㪍䋩䉥䊜䊒䊤䉹䊷䊦㩷䋨㪈㪐㪏㪐䋩ᘟᕈ㛽㜑ᕈ⊕ⴊ∛䊶ౝ⑼㗔ၞ䉁䈪ᐢ䈕䉎䊌䉨䉲䊦䋨㪪㪪㪩㪠䋩ศን䇭⿠Ḯ䊐䉢䊨䉰䊮䋨㪥㫆㫍㫆㩷㪥㫆㫉㪻㫀㫊㫂䋩㸢㪞㪪㪢䉣䊐䉢䉪䉰䊷㩿㪪㪥㪩㪠㪀㩷ᣣᧄ䋺↳⺧ਛ䇭䊪䉟䉴䊶ᔃ⤳⊒૞䇮⣖තਛ䈱ỗᷫ䋨⚂㪎㪌䋦䋩㩷䊒䊨䊒䊤䊉䊨䊷䊦䉳䊦䉼䉝䉷䊛㩷䋨㪈㪐㪎㪋䋩䉦䊒䊃䊒䊥䊦㩷䋨㪈㪐㪏㪇䋩䊨䉰䊦䉺䊮㩷䋨㪈㪐㪐㪋䋩䊒䊤䊋䉴䉺䉼䊮㩷䋨㪈㪐㪏㪐䋩㜞ⴊ࿶∝ਇᢛ⣂⁜ᔃ∝ᔃ╭᪪Ⴇᔃਇో㪁Ṷ⠪䈱⁛ᢿ䈫஍⷗ක㩷㩷≮㩷㩷⽸㩷㩷₂䊶␹⚻⑼䈱䇸㐽㎮∛᫟䇹䉕㐿᡼䈜䉎䉟䊙䉼䊆䊑㩷䋨㪉㪇㪇㪈䋩䉟䊮䊂䊤䊦䋨㜞ⴊ࿶䇮⁜ᔃ∝䇮ਇᢛ⣂䋩䇭䊪䉟䉴䊓䊦䊔䉾䉰䊷䋨㜞ⴊ࿶䇮⁜ᔃ∝䋩䇭↰ㄝක⮎R&D䊒䊨䉶䉴䈱⚫੺䉦䊒䊃䊥䊦䋨㜞ⴊ࿶䋩䇭㪙㪤㪪䊆䊠䊷䊨䉺䊮䋨㜞ⴊ࿶䋩䋨♧ዩ∛ᕈ⣢ᕈ䋩䇭䊜䊦䉪䊜䊋䊨䉼䊮䋨㜞⢽ⴊ∝䋩䇭ਃ౒䊶ᚻⴚ䈱ỗᷫ䋨⚂㪏㪇䋦ᷫ䋩䋨⢗ẩ≌䋧චੑᜰ⣺ẩ䋩䉺䉧䊜䉾䊃䋨㪟㪉㪀㩷䇭㪞㪪㪢䉥䊜䊒䊤䉹䊮㪆䉥䊜䊒䊤䊷䊦䋨㪧㪧㪠䋩䇭㪟㪸㫊㫊㫃㪼㩷㩿㪘㫊㫋㫉㪸㪱㪼㫅㪼㪺㪸㪀䊶䋵ᐕᓟ↢ሽ₸䈱ะ਄䋨㪐㪌䋦䋩䊶ᗵᨴᱫ੢₸䊶ᚻⴚ䈱ỗᷫᗵ䇭ᨴ䇭∝䊕䊆䉲䊥䊮⤳ེ⒖ᬀ䉰䉟䉪䊨䉴䊘䊥䊮㩷䋨㪈㪐㪏㪊䋩 䊶⤳ེ⒖ᬀ䉕น⢻䈮䋨․䈮⢄⤳䇮⣢⤳䋩䊶䉶䊐䉜䊨䉴䊘䊥䊮䇮䉨䊉䊨䊮䇮䊙䉪䊨䊤䉟䊄╬䈱᛫⩶೷⎇ⓥ䈱ၮ␆䊶഍⊛䈭᦭ലᕈ䋨㑐▵⎕უᛥ೙䋬−∩✭๺䋩㑐▵䊥䉡䊙䉼䉟䊮䊐䊥䉨䉲䊙䊑䋨㪈㪐㪐㪏䋩䉣䉺䊈䊦䉶䊒䊃㩿㪈㪐㪐㪏㪀䊃䉲䊥䉵䊙䊑䋨㪉㪇㪇㪌䋩䊧䊚䉬䊷䊄䋨᛫䊍䊃㪫㪥㪝㱍䊝䊉䉪䊨䊷䊅䊦᛫૕⵾೷䋩䇭㪚㪼㫅㫋㪺㫆㫉㪼␠䉣䊮䊑䊧䊦䋨ቢో䊍䊃ဳนṁᕈ㪫㪥㪝㱍㪆㪣㪫㱍䊧䉶䊒䉺䊷⵾೷䋩䇭㪧㪽㫀㫑㪼㫉␠䉝䉪䊁䊛䊤䋨᛫䊍䊃㪠㪣㪍䊧䉶䊒䉺䊷䊝䊉䉪䊨䊷䊅䊦᛫૕⵾೷䋩䇭ਛᄖ⵾⮎㪄ᄢ㒋ᄢቇ32䋩ක⮎R&D䊒䊨䉶䉴䈱⚫੺䋨᭎ⷐ䋩2䋩ක⮎R&D䊒䊨䉶䉴䈱⚫੺䋨᭎ⷐ䋩⚻ญᛩਈᤨ䈱⮎‛േᘒ䋨᭎⇛䋩ක⮎ຠ䈱⎇ⓥ㐿⊒䍪䍹䍎䈫⎇ⓥ㐿⊒⾌䋨㪡㪥㪧䋩೨ᦼ㐿⊒ഃ ⮎ ⎇ ⓥ䌾㪈ᐕ㪈䌾㪉ᐕ䌾㪈ం౞ᮡ䷸ 乡 丩⊛䷮ 乭 丶ಽ丩 乬 丈ൻሶ丶ว䶺上․丱‛䷯ቯ♽⊒⷗᭴▽丵丵ᮡ⹏⊛ଔಽ♽ሶ᭴䶺▽᦭↪
ᕈᬌ⸽丵ၮᧄ㛽ᩰ䶺ഃ಴㪈䌾㪊ం౞㪈䌾㪋ం౞㪌䌾㪉㪇ం౞⚂㪈ᐕ⚂㪈ᐕ⚂㪉㪇ం౞丩丶丈ൻว‛ᦨㆡൻ㪈䌾㪊ᐕ㐿⊒ൻว‛䶺⛉ㄟ䷋㪈䌾㪉ᐕ೨⥃ᐥ习乥乩⹜㛎╙乎⋧⥃ᐥ⹜㛎丵ᦨㆡൻ义⮎ല䵿૕ౝേᘒ䵿቟ోᕈ乊丵丵丵േേേ‛‛‛䶳䶳䶳䶺䶺䶺⮎૕቟ലౝో⏕േᕈ⹺ᘒ⏕⏕⹺⹺丵േ‛䶳䶺቟ోᕈ⹜㛎义习乥乩乊丵丵ஜஜᐽᐽੱੱ䶳䶳䶺䶺቟૕ోౝᕈേ⏕ᘒ⹺䶺⏕⹺ᓟᦼ㐿⊒⚂㪉㪅㪌ᐕ4䊶ᛩਈၮ೷⵾೷⸳⸘䊶ṁ⸃ᐲ䊶ൻቇ⊛቟ቯᕈ↳⺧ ᛚ⹺⚂㪉ᐕ㪉㪇䌾㪈㪇㪇ం౞㪌㪇䌾㪉㪇㪇ం౞╙乏⋧⥃ᐥ⹜㛎䊶ⴊẏਛỚᐲ(PK)䋺 ቟ోᕈ⹜㛎䇮⮎ല⮎ℂ⹜㛎䊶Ⱞ⊕⚿ว₸䊶⚵❱ਛỚᐲ⚻ญᛩਈ╙乐⋧⥃ᐥ⹜㛎䊶CYPઍ⻢቟ቯᕈ䋨ઍ⻢‛䋩䊶CYPಽሶ⒳ផቯ
䊶CYPઍ⻢㒖ኂ䊶෻ᔕᕈઍ⻢‛⢙᳝ਛឃᴭ
䊶Log P丵丵ᖚᖚ⠪⠪䶳䶳䶺䶺቟ᦨోㆡᕈ૶⏕↪
⹺㊂䶺᳿ቯ⢄⤳⮎‛ઍ⻢㉂⚛

䊶Caco-2ㅘㆊᕈ丵ᖚ⠪䶳䶺ലᨐᬌ⸽ዊ⣺ๆ෼⚵❱ಽᏓⴊᵹᮡ⊛⚵❱䊶P♧Ⱞ⊕䈱㑐ਈ๟ㄝ⚵❱䊶⢄⚦⢩↹ಽ䊶⢄એᄖ䈪䈱ઍ⻢䊶ઍ⻢㉂⚛⺃ዉ♮ਛឃᴭ5ዩਛឃᴭ
6

2䋩ක⮎R&D䊒䊨䉶䉴䈱⚫੺䋨᭎ⷐ䋩ഃ⮎䊒䊤䉾䊃䊖䊷䊛䌾1ᐕᮡ⊛ಽሶ䈱․ቯ䌈䌔䌓↢‛ᵴᕈ䋺䊶⚿วታ㛎

1䌾2ᐕ䍛䍖䍶䍎䍤䍻䍖䍼♽䈱᭴▽䍶䍎䍢䍼ൻว‛ត ⚝⮎ ല䋺䊶㫀㫅㩷㫍㫀㫋㫉㫆㩷⮎ല⹜㛎૕ౝേᘒ䋺*ⴊẏਛ቟ቯᕈ䊶ๆ෼ᕈ䋨⤑ㅘㆊᕈ䋩㪁㩷䍩䍢⢄䊚䉪䊨䉸䊷䊛ઍ⻢቟ቯᕈ㪁㩷㪚㫐㫇㒖ኂ䋨ᢙಽሶ⒳䋩
㪁㩷෻ᔕᕈઍ⻢‛䋨㪞㪪㪟䍢䍵䍍䍩䍽䍻䍖䍼䍏䍍䍜䍐䋩቟ ో ᕈ䋺
䊶ㆮવᲥᕈ㩿◲ᤃဳ㪘㫄㪼㫊㪀㪁㩷ᔃⴊ▤♽Ქᕈ䋨hERG䍟䍊䍦䍷⚿ว䋩‛ ᕈ䋺䊶⚐ᐲ䇮ṁ⸃ᐲ㩿᳓㪀䇮ಽ㈩ଥᢙ䇮䊶 䋳䌄᭴ㅧ੍᷹䋨ૐಽሶ䇮Ⱞ⊕⾰䋩
䊶 ㊀䈰ว䉒䈞䇮䍪䍅䍎䍭䍘䍪䍉䍏䈱᛽಴䊶 䍪䍅䍎䍭䍘䍪䍉䍏䍛䍖䍶䍎䍤䍻䍖䍼䊶 ⶄว૕⚿ว᭽ᑼ੍᷹2䋩ක⮎R&D䊒䊨䉶䉴䈱⚫੺䋨᭎ⷐ䋩㐿⊒⎇ⓥ䈮䈍䈔䉎ਥⷐᬌ⸛㗄⋡

1䌾3ᐕ

1ᐕ

ൻ ว ‛
ᦨ ㆡ ൻൻว‛䈱⛉䉍ㄟ䉂䍶䍎䍢䍼ൻว‛ഃ ಴⮎ ല䋺䊶㫀㫅㩷㫍㫀㫋㫉㫆㩷㩽㩷㫀㫅㩷㫍㫀㫍㫆⮎ല㩿㪧㪦㪚㪀⹜㛎૕ౝേᘒ䋺㪁ⴊẏਛ቟ቯᕈ䊶ๆ෼ᕈ䋨⤑ㅘㆊᕈ䋩㪁㩷䍩䍢⢄䊚䉪䊨䉸䊷䊛ઍ⻢቟ቯᕈ㪁㩷㪚㫐㫇㒖ኂ䋨฽ ෻ᔕᕈઍ⻢‛䋩㪁㩷෻ᔕᕈઍ⻢‛䋨㪞㪪㪟䍢䍵䍍䍩䍽䍻䍖䍼䍏䍍䍜䍐䋩㪁㩷䍏䍷䍪䍼䍮䍻䈫䈱⚿ว₸䋨䍩䍢䇮േ‛䋩㪁㩷㪧♧䍞䍻䍨䍽䍖⾰㑐ਈ䈱᦭ή቟ ో ᕈ䋺䊶ㆮવᲥᕈ㩿㪘㫄㪼㫊䇮䍭䍑䍛䍶䍻䍪䍉䍎䍭㪀㪁㩷ᔃⴊ▤♽Ქᕈ 䋨hERG㔚ᵹ䋬㪿㪜㪩㪞㪃㩷㪥㪸㪂䋬㪚㪸㪉㪂䍟䍊䍦䍷⚿ว䋩䊶৻⥸Ქᕈ䋨න࿁䋩‛ ᕈ䋺䊶⚐ᐲ䇮ṁ⸃ᐲ㩿᳓㪀䇮ಽ㈩ଥᢙ䇮䊶 ⶄว૕⚿ว᭽ᑼ੍᷹䋨⥄␠䌇䌁䋩䊶 ⚿ว⥄↱䍒䍦䍷䍕䍼䍎⸘▚㩿㪤㪤㪄㪧㪙㪪㪘㪀䊶 ಽሶ㑆⋧੕૞↪⸃ᨆ㩿㪝㪤㪦㪀䊶 ಽ㈩ଥᢙ䇮ṁ⸃ᐲ䇮Ქᕈ੍᷹⮎ല䋺䊶㫀㫅㩷㫍㫀㫋㫉㫆䇮㫀㫅㩷㫍㫀㫍㫆⮎ല૕ౝേᘒ䋺䊶Cyp㒖ኂ䈱♖ᩏ䋨 ᢙಽሶ⒳䋩
䊶䍩䍢⢄ઍ⻢㉂⚛⺃ዉ䊶䍵䍫䍼䍷૕䉕↪䈇䈢૕ౝേᘒ⹜㛎䋨ๆ෼䋺ⴊਛ᡼኿⢻Ớᐲ䇮ⴊਛᧂᄌൻ૕/ᵴᕈ૕Ớᐲ䋩䊶ਥઍ⻢‛䈱หቯ䋨in vitroઍ⻢‛䉕฽䉃䋩䊶䍵䍫䍼䍷૕䉕↪䈇䈢෻ᔕᕈઍ⻢‛䈱⏕⹺䊶ಽᏓ䋨⚵❱ਛỚᐲ䇮Ⱞ⊕⚿ว/ⴊ⃿⒖ⴕ䋩䊶ឃᴭ䋨ዩਛ䊶⢙᳝ਛឃᴭ䋩䊶㕖䈕䈦ᱤ㘃PK⹜㛎䊶TKᧄ⹜㛎䋨GLP䋩↪᷹ቯᴺ䈱䍨䍼䍶䍡䍼䍎䍚䍌䍻቟ోᕈ䋨㕖䌇䌌䌐䋩䋺䊶෻ᓳᛩਈᲥᕈ⹜㛎䋨䍵䍍䍢/ᄢേ‛䋩䊶ㆮવᲥᕈ⹜㛎䋨Ames䇮ᨴ⦡૕⇣Ᏹ)䊶቟ోᕈ⮎ℂ䋨ਛᨔ␹⚻♽䇮ᔃⴊ▤♽䇮๭ๆ♽䋩೨⥃ᐥ䌇 䌌 䌐⹜㛎䍩䍢ᦨ䉅❥↪䈘䉏䉎䈉䈧∛䈱േ‛⹏ଔ䊝䊂䊦䌾 ᒝ೙᳓ᵒ⹜㛎 䌾Phase III↳⺧

Phase IIa

Phase IIb⮎ല⏕⹺↪㊂෻ᔕᕈ䈱⏕⹺ᣢሽ⮎䊶䍪䍽䍵䍜䍬䍼䈫䈱Ყセ䍩䍢䈮䈍䈔䉎૕ౝേ䋨㪧㪢㪀ᦨㆡᛩਈ㊂䈱᳿ቯ㐳ᦼ቟ోᕈ䈱⏕ ⹺቟ోᕈ㪆േᘒ䈱⏕⹺േ‛ ૕ౝേᘒ䋧቟ోᕈ䊶෻ᓳᛩਈᲥᕈ⹜㛎䋨䍵䍍䍢㪆ᄢേ‛䋩䊶Ქᕈᯏᐨ⸃᣿䇮䍨䍼䍐䍓䍭䍎䍔䍎䈱ត⚝䊶ㆮવᲥᕈ⹜㛎䋨㪘㫄㪼㫊䇮ᨴ⦡૕⇣Ᏹ㪀䊶䍩䍢䈱ផቯਥઍ⻢‛䈱ㆮવᲥᕈ⹜㛎䋨㪘㫄㪼㫊㪀䊶⊹⤏ᗵ૞ᕈ䇮ዪᚲೝỗᕈ䇮శᲥᕈ䊶቟ోᕈ⮎ℂ䋨ਛᨔ␹⚻♽䇮ᔃⴊ▤♽䇮๭ๆ♽䋩ઍ⻢䊶⚵❱ਛ䈪䈱ઍ⻢䇮䊶ઍ⻢‛䈱ቯᕈ/ቯ㊂䇮䊶⮎‛ઍ⻢㉂⚛♽䈻䈱ᓇ㗀⋧੕૞↪
䊶ઍ⻢㉂⚛ಽሶ⒳/⋧੕૞↪
㐳ᦼ෻ᓳᛩਈᲥᕈ⹜㛎䋨䍵䍍䍢/ᄢേ‛䋩↢ᱺ⊒↢Ქᕈ⹜㛎䍔䍼 䍻 ේ ᕈ ⹜ 㛎ේ ⮎
⵾ ㅧ ᴺ䇮 ‛ ℂ ൻ ቇ ⊛ ᕈ ⾰䇮 ቟ ቯ ᕈ䇮 ⷙ ᩰ 㪆㩷⹜ 㛎 ᣇ ᴺ⵾ ೷⵾ ೷ ቇ ⊛ ᬌ ⸛䇮 ቟ ቯ ᕈ䇮 ㈩ ว ᄌ ൻ䇮 ⷙ ᩰ 㪆㩷⹜ 㛎 ᣇ ᴺ⿒ሼ: ዁᧪⊛䈮ಽሶ䉲䊚䊠䊧䊷䉲䊢䊮น⢻㗄⋡72䋩ක⮎R&D䊒䊨䉶䉴䈱⚫੺䋨᭎ⷐ䋩

Phase I82䋩ක⮎R&D䊒䊨䉶䉴䈱⚫੺䋨᭎ⷐ䋩ᶖൻ▤ๆ෼ᕈ䈱䉴䉪䊥䊷䊆䊮䉫㧔PAMPA㧕⮎‛䈱ᶖൻ▤ๆ෼ᕈ䉕ੱᎿ⤑䉕↪䈇䈩⹏ଔ䈜䉎ᣇᴺ
20cpd/weekήേ↢૕⤑ㅏㆱⴕേ
᳓ᵒⴕേੱᎿ⤑䊥䊮⢽⾰ੑ㊀⤑䉋䈛⊓䉍ⴕേ䊥䊮⢽⾰ṁᶧ䉕䊐䉞䊦䉺䊷䈮ᨴ䉂ㄟ䉁䈞䈢䉅䈱⮎‛ᶖൻ▤ౝ⣧⢽⾰ṁᶧ⚦⢩ౝ䉋䈛⊓䉍ⴕേ䊍䊃ዊ⣺䈪䈱ㅘㆊᕈ
LogPe(Human Jejunal)䊤䉾䊃䉕᳓䉕ḩ䈢䈚䈢౞╴䈮౉䉏ⴕേⷰኤ䇮౉᳓ᤨ䈚䈳䉌䈒䈲౞╴䈎䉌಴䉋䈉䈫䉅䈏䈒䈏䇮䉇䈏䈩ήേൻ⁁ᘒ䈫䈭䉎䇯⮎‛䉕ᛩਈ䈚䈩䇮䊤䉾䊃䈱ⴕേ䊌䉺䊷䊮䉕⺞䈼䈩⮎ല䉕್ᢿ䇯䌛ⷰኤ䈜䉎ⴕേ䊌䉺䊷䊮䌝䃂ήേ⛘ᦸ⁁ᘒ䋨䈉䈧⁁ᘒ䋩䉕෻ᤋ䃂ㅏㆱⴕേ⃻⁁䈎䉌⣕䈚䉋䈉䈫䈜䉎ᗧ᰼䈱⃻䉏䋨᛫䈉䈧૞↪䋩᳓ᵒⴕേ 䉶䊨䊃䊆䊮♽⮎೷䋨SSRI)䈲᳓ᵒⴕേ䉕Ⴧട䉋䈛⊓䉍ⴕേ䊉䊦䉝䊄䊧䊅䊥䊮♽⮎೷䋨SNRI)䈲䉋䈛⊓䉍ⴕേ䉕ჇടੱᎿ⤑䉕᜽䉖䈣⮎‛䈱ㅘㆊ䈱⒟ᐲ䉕⹏ଔ䈜䉎ੱᎿ⤑⮎‛⮎ᶧੱᎿ⤑䈪䈱ㅘㆊᕈ(LogPe䋬PAMPA䋩

2䋩ක⮎R&D䊒䊨䉶䉴䈱⚫੺䋨᭎ⷐ䋩⢄䊚䉪䊨䉸䊷䊛ઍ⻢቟ቯᕈ⹏ଔ♽ઍ⻢቟ቯᕈ䈫䈲䊶⚻ญᛩਈ䈚䈢⮎䈏ⴊᶧ䈮౉䉎೨䈮ಽ⸃䈜䉎੐䊶ⴊᶧ䈮ሽ࿷䈜䉎⮎䈏ᓢ䇱䈮ಽ⸃䈜䉎੐䊶ਥ䈮䉼䊃䉪䊨䊷䊛P450䈏⮎䈱ಽ⸃䈮㑐ਈ䈚䈩䈇䉎

2䋩ක⮎R&D䊒䊨䉶䉴䈱⚫੺䋨᭎ⷐ䋩䊍䊃⢄㪧㪋㪌㪇䋨㪚㪰㪧㪀ઍ⻢䈱㒖ኂઍ⻢㉂⚛䈮⿠࿃䈜䉎⮎‛㑆⋧੕૞↪䈱㪐㪇㩼䈲䌃䌙䌐䈮㑐ㅪ䌃䌙䌐ઍ⻢㒖ኂ૬↪⮎䈱ⴊਛỚᐲ਄᣹⚻ญᛩਈઍ⻢቟ቯᕈ䈏⦟䈒䈭䈇႐ว䊶ⴊᶧ䈮⮎䈏ⴕ䈎䈭䈇䋨↢‛ቇ⊛೑↪₸䈏

PAMPA䋺Parallel Artificial Membrane Permeability Assay 10㕒⣂ౝᛩਈઍ⻢⚻ญᛩਈ⢄਄Ꮢ⮎䈱ઍ⻢䈮ነਈ䈜䉎㪚㪰㪧ಽሶ⒳䈱ഀวⴊᶧૐ䈇䋩CYP3A4㪚㪰㪧㪉㪛㪍䊶ⴊᶧਛ䈎䉌⮎䈏䈜䈓䈮ή䈒䈭䈦䈩䈚䉁䈉䋨ᶖᄬඨᷫᦼ䈏⍴䈇䋩㪚㪰㪧㪊㪘㪋⃻࿷䈱⹏ଔ♽

20cpd/week37͠ ଻᷷䊶⢄⤳䈪ઍ⻢䈮㑐ଥ䈜䉎䊚䉪䊨䉸䊷䊛䈮⮎‛䈣䈔ಽ⸃䈚䈩䈇䉎䈎䉕⹏ଔ㪚㪰㪧㪉㪚㪏㪚㪰㪧㪉㪚㪐䉕ട䈋䈩䇮৻ቯᤨ㑆ᓟ䈮䈬䉏䈣䈔ಽ⸃䈚䈩䈇䉎䈎䉕⹏ଔ㜞ᰴ⹏ଔ♽䊶⢄⚦⢩䈮⮎‛䉕ട䈋䈩䇮৻ቯᤨ㑆ᓟ䈮䈬䉏LC-MS䈪᷹ቯ㪚㪰㪧㪉㪚㪈㪐㪚㪰㪧㪈㪘㪉㪚㪰㪧㪉㪜㪈㪚㪰㪧㪉㪘㪍⮎‛+䊚䉪䊨䉸䊷䊛12

2䋩ක⮎R&D䊒䊨䉶䉴䈱⚫੺䋨᭎ⷐ䋩

2䋩ක⮎R&D䊒䊨䉶䉴䈱⚫੺䋨᭎ⷐ䋩㉂⚛⺃ዉ⹏ଔ♽CYP㒖ኂ⹏ଔ♽㉂⚛⺃ዉ䈫䈲䊶⮎䈱ಽ⸃䈮㑐ਈ䈜䉎㉂⚛䈏⮎೷䈮䉋䈦䈩Ⴧ䈋䉎䈖䈫CYP㒖ኂ䈫䈲䊶⮎䈱ಽ⸃䈮㑐ਈ䈜䉎㉂⚛䈮ኻ䈜䉎㒖ኂ⢻ജ䊶⮎‛㑆⋧੕૞↪䈫䉅๭䈳䉏䈩䈇䉎•೽૞↪䈮ಽ㘃䈘䉏䉎੐䉅䈅䉎䊶⮎‛㑆⋧੕૞↪䈱৻䈧䈮ಽ㘃䈘䉏䉎䋨CYP㒖ኂ䈱ㅒ䋩•೽૞↪䈮ಽ㘃䈘䉏䉎੐䉅䈅䉎ߘߩઁCYP䉕㒖ኂ䈜䉎႐วๆ෼•૬↪⮎䈱ⴊਛỚᐲ䈏㜞䈒䈭䉍ㆊ䈑䇮૬↪⮎䈱೽૞↪䈏಴䉇䈜䈒䈭䉎•ᛚ⹺↳⺧䈏⹺䉄䉌䉏䈭䈇น⢻ᕈ䈏䈅䉎⃻࿷䈱⹏ଔ♽ઍ⻢
( 37% )㉂⚛⺃ዉ䈏⿠䈖䉎䈫⮎ജቇ

P450( 96% )⋧੕૞↪(256଀)ߩ
ᯏ᭴೎ಽ㘃ઍ⻢ߢߩ⋧੕૞↪
(100଀)ߩઍ⻢㉂⚛೎ಽ㘃37͠ ଻᷷

LC-MS䈪᷹ቯ

20cpd/week૬↪㐿ᆎ•૬↪⮎䈱ⴊਛỚᐲ䈏ૐ䈒䈭䉍䇮૬↪⮎䈱⮎ല䈏ᶖᄬ䈜䉎•ᛚ⹺↳⺧䈏⹺䉄䉌䉏䈭䈇น⢻ᕈ䈏䈅䉎⃻࿷䈱⹏ଔ♽LC-MS䈪㉂⚛ᵴᕈ᷹ቯ37͠ ᢙᣣ଻᷷PCR䈪mRNA᷹ቯ

P-Glycoprotein䋨P-gp䋩⹏ଔ♽
P-gp䈫䈲

䊶䉺䊮䊌䉪䈫⚿ว䈚䈩䈇䈭䈇⮎‛䈏૞↪䉕␜䈜•ਥ䈮ⴊẏ䉝䊦䊑䊚䊮䈏⚿ว䉺䊮䊌䉪䈫䈭䉎⮎‛䌁⃻࿷䈱⹏ଔ♽

0.2cpd/week2䋩ක⮎R&D䊒䊨䉶䉴䈱⚫੺䋨᭎ⷐ䋩䉺䊮䊌䉪⚿ว䈫䈲䊶ⴊਛ䈮ሽ࿷䈜䉎⮎‛䈱䈉䈤䈬䉏䈣䈔䈏䉺䊮䊌䉪䈫⚿ว䈚䈩䈇䉎䈎䉕⹏ଔ䈜䉎䷾丱丐䷮⾰䷾丱丐䷮⾰䉺䊮䊌䉪䈮⚿ว䈚䈩䈇䈭䈇䋨㕖⚿วဳ䋩⮎‛䈏ᮡ⊛ಽሶ䈫૞↪䈜䉎⮎‛䌂䷾丱丐䷮⾰⮎ല⊒⃻ᦨዊỚᐲ•ᣂ㞲⢄⚦⢩䈮3-4ᣣ㑆⮎‛䉕ട䈋䇮ઍ⻢㉂ ઍ⴫⮎+⹏ଔ⮎‛⢄⚦⢩⚛䈱mRNA㊂䈫㉂⚛ᵴᕈ䉕᷹ቯ䉺䊮䊌䉪⚿ว⹏ଔ♽•ⴊਛỚᐲ䈏㜞䈇䈱䈮⮎ല䈏಴䈭䈇•ઁ䈱⮎䈫૬↪䈚䈢႐ว䇮೽૞↪䈏಴䉎䋨⮎‛㑆⋧੕૞↪䋩น⢻ᕈ䈏䈅䉎Ქᕈ⊒⃻ᦨዊỚᐲᴦ≮ၞ㜞ᰴ⹏ଔ♽

2䋩ක⮎R&D䊒䊨䉶䉴䈱⚫੺䋨᭎ⷐ䋩䉺䊮䊌䉪⚿ว䈏㜞䈇⮎‛䈲ਛᲥၞ•⢄ၭ㙃⚦⢩䈮3-4ᣣ㑆⮎‛䉕ട䈋䇮ઍ⻢㉂⚛䈱mRNA㊂䈫㉂⚛ᵴᕈ䉕᷹ቯઍ⴫⮎+⹏ଔ⮎‛䊚䉪䊨䉸䊷䊛•⹏ଔ⮎‛䈱ઍ⻢‛䈏ಽ⸃䉕㒖ኂ䈜䉎䈎䉕⹏ଔ䋨ઍ⻢ଐሽ⊛㒖ኂ䋩㒖ኂ೷⺃ዉ೷ ήലၞ•䊚䉪䊨䉸䊷䊛䈮ઍ⴫⊛⮎䈫⹏ଔ⮎‛䉕ട䈋䈩䇮ઍ⴫⮎䈱ಽ⸃䉕㒖ኂ䈜䉎䈎䉕⹏ଔ䋨䋶⒳㘃䈱ઍ⴫⮎䋩㜞ᰴ⹏ଔ♽⮎‛ⴊਛỚᐲಽᏓ ਇ᣿ឃᴭ䷾丱丐䷮⾰ᐔⴧㅘᨆฃኈ૕䊶ABC䋨ATP-binding cassette䋩䊃䊤䊮䉴䊘䊷䉺䊷䊐䉜䊚䊥䊷䈮ዻ䈜䉎ಽሶ㊂⚂17ਁ䈱12࿁⤑⽾ㅢဳ♧䉺䊮䊌䉪⾰䊶ATP䉕೑↪䈚䈩ၮ⾰䉕⚦⢩ౝ䈎䉌⚦⢩ᄖ䈻䈫⢻േ⊛䈮ឃ಴䈜䉎䊘䊮䊒䈪䈅䉎䇯䊶⣖䇮ዊ⣺䇮⢄⤳䈮⊒⃻䈚䈩䈇䉎

P-gp䈱ၮ⾰䈫䈭䉎䈫䊶⣖䈮ಽᏓ䈚䈭䈇䊶ᶖൻ▤ๆ෼䈏ᖡ䈒䈭䉎

P-gp䉕㒖ኂ䈜䉎䈫
⮎‛B䈲䉺䊮䊌䉪⚿ว䈏㜞䈇䈢䉄⮎ല⊒⃻䈮㜞䈇Ớᐲ䈏ᔅⷐ

LC-MS䈪᷹ቯP-Glycoprotein䊶ᶖൻ▤ๆ෼䈏⦟䈒䈭䉍䈜䈑䉎䊶⣖䈻⮎‛䈏ᄙ䈒ⴕ䈐೽૞↪䈏಴䉎ෂ㒾ᕈ䈏㜞䈒䈭䉎

5cpd/week•ⴊᷡ䈫⹏ଔ⮎‛䉕ᐔⴧㅘᨆ䈚䇮⚿ว₸䉕▚಴ᬌ⸛ਛ⹏ଔ♽

P-gp䈱⹏ଔ♽•ⴊẏ䉝䊦䊑䊚䊮䇮㉄ᕈ♧䉺䊮䊌䉪䉕䉶䊮䉰䊷䈮⚿ว䈘䈞䇮ⷫ๺ᕈ䉕᷹ቯ䈚䇮⚿ว₸䉕੍ᗐ

䊶P-gp䉕⊒⃻䈘䈞䈢⚦⢩⤑䉕ㅘㆊ䈜䉎ㅦᐲ䈱Ყ䈪ၮ⾰䈎ุ䈎䉕್ቯ

2䋩ක⮎R&D䊒䊨䉶䉴䈱⚫੺䋨᭎ⷐ䋩ャㅍᜂ૕䋨䊃䊤䊮䉴䊘䊷䉺䊷䋩⹏ଔ♽䊃䊤䊮䉴䊘䊷䉺䊷䈫䈲䊶⮎‛䉇ૐಽሶ‛⾰䉕⚦⢩䈮ข䉍ㄟ䉖䈣䉍䇮ឃ಴䈚䈢䉍䈜䉎䉺䊮䊌䉪⾰䈱ฬ⒓䊶ක⮎ຠ䈮㑐ㅪ䈜䉎䉅䈱䈲ABCဳ䈫SLCဳ䈱䋲⒳㘃䈅䉎䇯䊶ᶖൻ▤䇮⢄䇮⣢䇮⣖䈪䈱ᓎഀ䈏㊀ⷐ2䋩ක⮎R&D䊒䊨䉶䉴䈱⚫੺䋨᭎ⷐ䋩䍖䍼䍷䍞䍟䍓䍻䋨GSH䋩䍢䍵䍍䍩䍽䍻䍖䍼䍏䍍䍜䍐↢૕㜞ಽሶ䈮౒᦭⚿ว䈜䉎䈖䈫䈪䋬⢄㓚ኂ䋨഍∝⢄Ἳ╬䋩䋬⊒䈏䉖䋬௅ᄸᒻᕈ╬䈱ේ࿃䈫䈭䉎෻ᔕᕈઍ⻢‛䈱ᬌ಴ᴺ䋨ቯᕈ⊛䋩⢄䍮䍖䍹䍝䍎䍯䈫⮎‛䉕䍐䍻䍕䍋䍫䍼䍎䍚䍌䍻䈚䈢䈫䈐䈮↢ᚑ䈜䉎෻ᔕᕈ䈮ን䉂䋬ᭂ䉄䈩ਇ቟ቯ䈭෻ᔕᕈઍ⻢‛䉕䋬GSH䈪䍢䍵䍍䍪䍽䈚቟ቯൻ䈚䈩ᬌ಴䈜䉎ᣇᴺ䋨ቯᕈ⊛䋩• ᡼኿ᕈห૏૕䋨RI䋩ᮡ⼂૕䈏ਇⷐ䋬ត⚝Ბ㓏䈪䈱䍛䍖䍶䍎䍤䍻䍖䍼䈏น⢻䊶⣖䈮ಽᏓ䈚䈭䈇䇮ᶖൻ▤ๆ෼䈏ᖡ䈒䈭䉎䋨ABCဳ䋩䊶⢄⤳䈮㓸Ⓧ䈜䉎䇮ዩ䈮ឃ಴䈜䉎䋨SLCဳ䋩⮎‛䊃䊤䊮䉴䊘䊷䉺䊷䉕㒖ኂ䈜䉎䈫೽૞↪䈏಴䉎ෂ㒾ᕈ䈏㜞䈒䈭䉎ၮ⾰䈎ุ䈎䉕್ቯ䋨ABCဳ䋩䊶⊒⃻䈘䈞䈢⚦⢩䈱ਛ䈮ൻว‛䈏⫾Ⓧ䈜䉎䈎ุ䈎䉕್ቯ䋨SLCဳ䋩

GSH

⮎‛ઍ⻢
㉂⚛

䊶ᶖൻ▤ๆ෼䈏⦟䈒䈭䉍䈜䈑䉎䋨ABCဳ䋩䊶⢄⤳䈮ⴕ䈎䈭䈒䈭䉍䇮ⴊẏਛỚᐲ䈏਄䈏䉎䋨SLCဳ䋩䊶⊒⃻䈘䈞䈢⚦⢩⤑䉕ㅘㆊ䈜䉎ㅦᐲ䈱Ყ䈪䊍䊃㪧㪄㪾㫇㜞⊒⃻⚦⢩⤑•䊃䊤䊮䉴䊘䊷䉺䊷䈱ၮ⾰䈫䈭䉎䈫෻ᔕᕈઍ⻢‛

0*%1%* 䊃䊤䊮䉴䊘䊷䉺䊷⊒⃻⚦⢩ABCဳ䈱ၮ⾰䈪䈅䉎႐ว䇮ㅘㆊㅦᐲ䈱Ყ䋨⿒䈫㕍䈱Ყ₸䋩䈏ᄢ䈐䈒䈭䉎
SLCဳ䈱ၮ⾰䈪䈅䉎႐ว䇮⚦⢩ౝ䈱Ớᐲ䈏㜞䈒䈭䉎↢ᚑ䈚䈢GSHઃട૕䉕
LC-MS䈪ᬌ಴

SGGSHઃട૕

0*%1%* 0%1%* 

CYP2E1䍏䍜䍢䍏䍮䍧䍪䍈䍻䈱଀䊃䊤䊮䉴䊘䊷䉺䊷䈱⹏ଔ♽P-gp䈱ၮ⾰䈪䈅䉎႐ว䇮ㅘㆊㅦᐲ䈱Ყ䋨⿒䈫㕍䈱Ყ₸䋩䈏ᄢ䈐䈒䈭䉎

*1GSH

1*1

1*0*1෻ᔕᕈઍ⻢‛

0* 

1GSH䋺-glutamyl-cysteinyl-glycine

1*

1*051

䍏䍜䍢䍏䍮䍧䍪䍈䍻-GSHઃട૕
18

2䋩ක⮎R&D䊒䊨䉶䉴䈱⚫੺䋨᭎ⷐ䋩

2䋩ක⮎R&D䊒䊨䉶䉴䈱⚫੺䋨᭎ⷐ䋩ㆮવᲥᕈ㩿㪞㪼㫅㫆㫋㫆㫏㫀㪺㫀㫋㫐㪀䈕䈦ᱤ㘃䉕↪䈇䉎ዊᩭ⹜㛎ㆮવሶ䈮૗䉌䈎䈱்ኂ䉕ਈ䈋䉎䈖䈫䈅䈦䈩䈲䈭䉌䈭䈇Ქᕈ䈱৻䈧㪛㪥㪘៊்⊒䈏䉖‛⾰⋡⊛䋺 േ‛୘૕䈮ኻ䈜䉎ᨴ⦡૕⇣Ᏹ⺃⊒ᕈ䈱᦭ή䉕⺞䈼䉎⹏ଔ䋺 ᄢ⣽㛽䈱㛽㜑⚦⢩ਛ䈮ዊᩭ䋨䋽ᨴ⦡૕䈱᭴ㅧ䊶ಽⵚ⇣Ᏹ䈮䉋䉎ᨴ⦡૕ᢿ 䋩䉕᦭䈜䉎ᐜ⧯⿒ⴊ⃿䈱ഀว䈎䉌ᨴ⦡૕⇣Ᏹ䈱᦭ή䉕⺞䈼䉎㛽㜑ㆮવሶ⓭ὼᄌ⇣૕⚦⢩٨٨٨࡮⊒߇ࠎㆮવᲥᕈ‛⾰↢ᱺ⚦⢩ᨴ⦡૕⇣Ᏹᐜ⧯ ψᚑᾫ⿒ⴊ⃿࡮ᄸᒻ㧘ᵹ↥࡮⺋ߞߚᖱႎߩㆮવዊᩭ⚦⩶䉕૶䈉Ames⹜㛎േ‛䈱⚦⢩䉕૶䈉ᨴ⦡૕⇣Ᏹ䋨ዊᩭ䋩⹜㛎
192䋩ක⮎R&D䊒䊨䉶䉴䈱⚫੺䋨᭎ⷐ䋩

202䋩ක⮎R&D䊒䊨䉶䉴䈱⚫੺䋨᭎ⷐ䋩቟ోᕈ⮎ℂ⹜㛎㩿ᔃⴊ▤♽㪀ᔃቶ╭(⚦⢩)䈱ᵴേ㔚૏䈫䉟䉥䊮㔚ᵹ䈱᷹ቯ䌾 㪨㪫㑆㓒ᑧ㐳䈫⓭ὼᱫ 䌾Ca++ᱜᏱᵴേ㔚૏ (in vitro)K+⁚‷⁄‹‒ᩓ්ᚾ᬴

Ca channelhERGchannel䋨Ikr)

ᔃ㔚࿑ (in vivo)

Na+

䌑䌔ᑧ㐳

K+
䋨IKr䋩

Na channel

TQᱜᏱ䈭㪨㪫㑆㓒䋨㪘㪧㪛㪀㪨㪫㑆㓒䋨㪘㪧㪛㪀ᑧ㐳

hERG㔚ᵹ⹜㛎䋨䊌䉾䉼䉪䊤䊮䊒ᴺ䋩ᔃቶᕈਇᢛ⣂

Action Potential Duration 90 (APD 90)

㪨㪫㑆㓒䋨㪘㪧㪛㪀䈏ᑧ㐳䈜䉎䈫䋬ਇᢛ⣂䈱ਛ䈪䉅ᦨ䉅㊀◊䈭ᔃቶᕈਇᢛ⣂䈏⿠䈖䉍䋬⓭ὼᱫ䈮䈧䈭䈏䉎䋮
HERG䋺Human ether-a-go-go related gene 䋻 ㆃᑧᢛᵹ K+ 䉼䊞䊈䊦䈱䈉䈤ᕆㅦ䈭ᵴᕈൻ䉕␜䈜
hERG (IKr) channel 䉕䉮䊷䊄䈜䉎ㆮવሶhERG channel෇ѣᩓˮᚾ᬴≋ઇЈ∈∑∈⇩⇮ʐ᪽ሂ≌

21hERGㆮવሶዉ౉⚦⢩䉕↪䈇䈢⚿วᕈ⹜㛎䊝䊦䊝䉾䊃ᔃ╭⚦⢩䉕૶䈉hERG㔚ᵹ⹜㛎

3䋩ഃ⮎䈮䈍䈔䉎ಽሶ⸘▚䋨⃻⁁䋩

22䊥䊷䊄ൻว‛䈱⸳⸘ૐಽሶൻቇ᭴ㅧDBᮡ⊛䉺䊮䊌䉪3D᭴ㅧ

㘃✼䉺䊮䊌䉪3D᭴ㅧ

~700ਁൻว‛HTSᮡ⊛䉺䊮䊌䉪੍᷹3D᭴ㅧ

3D᭴ㅧ↢ᚑ
Concord etc.

ⶄว૕3D᭴ㅧ䋯ⶄว૕੍᷹3D᭴ㅧൻว‛ಽ㘃
Pharmacophore᛽಴ഃ⮎䈮䈍䈔䉎ಽሶ⸘▚䋨⃻⁁䋩

Catalyst
Pharmacophore Screening

Docking Screening
AutoDock

Catalyst䉮䊮䊏䊠䊷䉺 䉲䊚䊠䊧䊷䉲䊢䊮䊥䊷䊄ൻว‛୥⵬วᚑHTS: High-Throughput Screening
23⹏ଔ䊥䊷䊄ൻว‛24䈅䉎਎⇇ᄢᚻ⵾⮎ળ␠䈱䌈䌔䌓䈱ታ❣䋪

3䋩ഃ⮎䈮䈍䈔䉎ಽሶ⸘▚䋨⃻⁁䋩

Pharmacophore᛽಴䈫䉴䉪䊥䊷䊆䊮䉫 (Catalyst)
䌾KDR㒖ኂ೷(⣲≌ⴊ▤ᣂ↢䈱㒖ኂ)䌾
⧐㚅Ⅳ䋪 C&EN, 82, 23-32, 2004᳓⚛⚿ว䊄䊅䊷
IC50=0.003M⹏ଔൻว‛ᚑഞ⏕₸䊥䊷䊄ᢙ䋯ᮡ⊛䊥䊷䊄䈱ᵴᕈ䋱䋹䋹䋶䋱䋹䋹䋹䋲䋰䋰䋳䋲䋰䋰䋴ᐕ䋱䋰ਁ䋲䋰䋦䋱㪅䋰㪊㪃㪇㪇㪇䌮㪤䋴䋳ਁ䋵䋰䋦䋱㪅䋷㪋㪇㪇䌮㪤䋶䋲ਁ䋵䋸䋦䋱㪅䋹㪈㪇䌮㪤䋱䋰䋵ਁ䋶䋵䋦䋲㪅䋰㪈㪇䌮㪤⇹᳓ၮ᳓⚛⚿ว䉝䉪䉶䊒䉺䊷

10458
ൻว‛KDR㒖ኂ೷
䊃䊧䊷䊆䊮䉫䉶䉾䊃 28ൻว‛䋱.䋳ం౞/䋱♽KDR (kinase insert domain receptor䋩䋺ⴊ▤ౝ⊹⚦⢩Ⴧᱺ࿃ሶฃኈ૕䈱䉨䊅䊷䉷ㇱ૏

Hui Yu, et al., Bioorg. Med. Chem. Lett., 2007, 17, 2126–2133
26253䋩ഃ⮎䈮䈍䈔䉎ಽሶ⸘▚䋨⃻⁁䋩

IC50=30M3䋩ഃ⮎䈮䈍䈔䉎ಽሶ⸘▚䋨⃻⁁䋩

Pharmacophore Screening

Pharmacophore Screening (Catalyst)

䌾 PTP1B 㒖ኂ‛⾰䋨㪉ဳ♧ዩ∛ᴦ≮⮎䋩 䌾䋨䊖䉴䊐䉜䉺䊷䉷䋩ConformationalDatabase⇹᳓ᕈ⇹᳓ᕈin silico䊐䉜䊷䊙䉮䊐䉤䉝䉴䉪䊥䊷䊆䊮䉫䊝䊂䊦᭴ㅧ䊒䊨䊁䉟䊮䉼䊨䉲䊮䊖䉴䊐䉜䉺䊷䉷

Positiveionizable

Focused Library
Aromatic
Positiveionizable䉺䊮䊌䉪⾰䈱ේሶAcceptor᳓⚛⚿ว㪘㪺㪺㪼㫇㫋㫆㫉᳓⚛⚿ว㪘㪺㪺㪼㫇㫋㫆㫉䉺䊮䊌䉪⾰䈱ේሶIC50= 0.061M

HydrophobicDonor
Donor
Acceptorⶄว૕⚿᥏᭴ㅧAssay䊐䉜䊷䊙䉮䊐䉤䉝

HTS䊍䉾䊃ൻว‛䈱଀
IC50= 0.89M䊐䉜䊷䊙䉮䊐䉤䉝૞ᚑ
273䋩ഃ⮎䈮䈍䈔䉎ಽሶ⸘▚䋨⃻⁁䋩

Docking Screening (AutoDock)

283䋩ഃ⮎䈮䈍䈔䉎ಽሶ⸘▚䋨⃻⁁䋩⋥ㄭ䈱 in silico Screening 䈱଀䌾PRL-3㒖ኂ೷䋨᛫䈏䉖೷䋩䌾䋨䊖䉴䊐䉜䉺䊷䉷䋩

85,000compounds

compound 1

PRL-1 X✢⚿᥏᭴ㅧ
pdb: 1XM2䊖䊝䊨䉳䊷䊝䊂䊥䊮䉫
PRL-3੍᷹᭴ㅧ

䊄䉾䉨䊮䉫
191 hits

AutoDock䊶೨Ḱ஻: ૐಽሶ3D᭴ㅧ↢ᚑ䊶ㆮવ⊛䉝䊦䉯䊥䉵䊛䊶AMBER䉕ᡷ⦟䈚䈢䉣䊈䊦䉩䊷in vitro
Enzyme Assay
12 compounds
10~50M
Predicted binding mode ofcompound 1 (IC50=13.3M)

H.Park et al.,Bioorg.Med.Chem.Lett. 2008, 18, 2250-2255.
29∔ᖚ䉸䊐䊃䉡䉢䉝ᬌ⚝ኻ⽎ᢙᬌ⚝䊍䉾䊃ᢙᵴᕈ
ൻว‛ᢙ

ᵴᕈ䈱ᒝ䈘

⺰ᢥ

≸

AutoDock

85000

191

1210䌾50M

(1)

EF

ᗵᨴ∝

AutoDock

10000

194

M

(2)

KDR
*ᮡ⊛3D᭴ㅧ䈭䈚≸㩿ⴊ▤ᣂ↢㪀

Catalyst

10458

20

130M

(3)

17㱎-HSD1

੃≸Catalyst

34004214

4

6䌾50㱘M(4)

Cathepsin S⥄Ꮖ఺∉∔ᖚ

Catalyst

2664754

157Ki < 15M

(5)

AdoMetDC

≸

GLIDE

1990

133

1M(6)CCR5HIV䉡䉞䊦䉴

GOLD, Surflex

162031659

1010M(7)

MCH-R1⢈ḩ

ICM

1870841296ᮡ⊛ಽሶ
PRL-3(S-adenosylmethionine decarboxylrase)

References(1) Bioorg.Med.Chem.Lett. 2008, 18, 2250-2255.
(2) Bioorg.Med.Chem. 2008, 16, 7225–7233.
(3) Bioorg.Med.Chem.Lett. 2007, 17, 2126–2133.
(4) J.Med.Chem. 2008, 51, 4188-4199.

Ki = 7-20M (8)(5) J.Chem.Inf.Model. 2007, 47, 1897-1905.
(6) J.Med.Chem. 2007, 50, 1294-1303.
(7) J.Chem.Inf.Model. 2008, 48, 1693-1705.
(8) J.Med.Chem. 2008, 51, 581-588.

30

3䋩ഃ⮎䈮䈍䈔䉎ಽሶ⸘▚䋨⃻⁁䋩䊥䊷䊄ൻว‛䈱ᦨㆡൻᮡ⊛䉺䊮䊌䉪3D᭴ㅧ

㘃✼䉺䊮䊌䉪3D᭴ㅧ

3䋩ഃ⮎䈮䈍䈔䉎ಽሶ⸘▚䋨⃻⁁䋩

Docking Simulation
䌾Lck㒖ኂ‛⾰䈱⸳⸘(1)䌾

䊥䊷䊄ൻว‛

Lck䈫䈲䇮T⚦⢩ฃኈ૕䈫ળว䈚䇮䉰䉟䊃䉦䉟䊮↥↢䈍䉋䈶T⚦⢩Ⴧᱺ䉲䉫䊅䊦䈱⿠ὐ䈫䈭䉎䉨䊅䊷䉷ᮡ⊛䉺䊮䊌䉪੍᷹3D᭴ㅧ

Docking Simulation
docking(⥄␠)ಽ㈩ଥᢙ੍᷹

Derek
Toxicity DB

ACD LogD⚿ว⥄↱䉣䊈䊦䉩䊷⸘▚ MM-PBSAಽሶ㑆⋧੕૞↪⸃ᨆ ProteinDF/FMO䊖䊝䊨䉳䊷䊝䊂䊥䊮䉫Ქᕈ੍᷹䉮䊮䊏䊠䊷䉺 䉲䊚䊠䊧䊷䉲䊢䊮⸳⸘䈚䈢ൻว‛⮎ല(in vitro, in vivo)૕ౝേᘒ቟ోᕈ
‛ᕈวᚑ㐿⊒(୥⵬)‛⾰⹏ଔ

Inactiveဳ HCK⚿᥏᭴ㅧ䋨PDB code䋺1QCF䋩
Inactiveဳ LCK䊝䊂䊦᭴ㅧ
31

Docking Simulation3䋩ഃ⮎䈮䈍䈔䉎ಽሶ⸘▚䋨⃻⁁䋩

3䋩ഃ⮎䈮䈍䈔䉎ಽሶ⸘▚䋨⃻⁁䋩

䌾Lck㒖ኂ‛⾰䈱⸳⸘(2)䌾

O

ൻว‛A’H N
䋨25nM䋩

2ONH

䊄䉾䉨䊮䉫

NH F

ൻว‛B H N
䋨3nM䋩

OCH3ൻว‛A䋨144nM䋩

ᵴᕈ㪈㪇㪇୚⴫㕙䈱⦡(⿒: ⷫ᳓ᕈ䇮✛: ⇹᳓ᕈ)

22CH3HTS䊍䉾䊃: IC50=39nM⋧੕૞↪᭽ᑼ䈲ਇ᣿

NH2OONH

ൻว‛A H N
䋨144nM䋩䌾㉂⚛㒖ኂ೷䈱ᦨㆡൻ䌾

O

NH2O

Docking Simulation᜝ᒐౝ䊶䊶䊶㉂⚛㒖ኂ IC50O

NH232OFൻว‛B䋨3nM䋩

Glu317Glu317

Met319

Met319ಽሶ㑆⋧੕૞↪䈱ᛠី
IC50=39nM⇹᳓䊘䉬䉾䊃

㛽ᩰᄌ឵
IC50=13nM

ᵴᕈჇᒝIC50=0.4nM䊘䉬䉾䊃䈱䈒䈿䉂䉕೑↪

ᮡ⊛㉂⚛

3䋩ഃ⮎䈮䈍䈔䉎ಽሶ⸘▚䋨⃻⁁䋩ൻว‛A’䋨25nM䋩

ൻว‛B䋨3nM䋩

33343䋩ഃ⮎䈮䈍䈔䉎ಽሶ⸘▚䋨⃻⁁䋩

MM-PBSAᴺ䈱ㆡ↪଀kcal/mol䌾 ⚿ว⥄↱䉣䊈䊦䉩䊷Ꮕ䈫㉂⚛㒖ኂᵴᕈ䈱㑐ଥ 䌾kcal/mol䋨䍕䍣䍎䍜䍼䋩''G kcal/mol䋨⸘▚୯䋩

Receptor

㪍

⸘
▚
୯


Ligand'Gbind㪄㪉㪄㪍㪇Complex

Cathepsin D**⚿ว⥄↱䉣䊈䊦䉩䊷㪉

Estrogen Receptor*

㪄㪋㪇'Gbind+㪈㪇

MM-PBSAᴺ䈱⸘▚⚿ᨐ㩷
MM-PBSAᴺ䈱⸘▚⚿ᨐ㪄㪏㪇

GComplex  (GReceptor  GLigand )㩷ൻว‛A䋨144nM䋩

1n㪇

Cathepsin D10n
㪈

100n
㪉

1㱘䇭䇭䇭䇭䇭䇭䇭䇭䇭10㱘/mol㪊㪋ታ㛎୯䋨IC50)

MM-PBSAᴺ㪩㪉㩷㪔㩷㪇㪅㪏㪎㪎㪌㪄㪍ṁ⾰䈱⥄↱䉣䊈䊦䉩䊷
Molecular Mechanics

㪄㪈㪇
㪌

㪍

㪎

㪏

pIC50䋨㒖ኂᵴᕈ䈱ታ᷹୯䋩㪐

'G'EMM  T'S  'GPBSA
J. Med. Chem., 45, 1412 (2002), S. Huo et al.
᳓๺⥄↱䉣䊈䊦䉩䊷㕒㔚㗄䉕Poisson-Boltzmann䇮㕖㕒㔚㗄䉕Solvent Accessible Surface Area
3536

3䋩ഃ⮎䈮䈍䈔䉎ಽሶ⸘▚䋨⃻⁁䋩3䋩ഃ⮎䈮䈍䈔䉎ಽሶ⸘▚䋨⃻⁁䋩

LUMO䉣䊈䊦䉩䊷䈮䉋䉎ⴊẏਛ቟ቯᕈ䈱੍᷹

HOMO䉣䊈䊦䉩䊷䈮䉋䉎ᄌ⇣ේᕈ䈱੍᷹
NH2NHOHNHDNA-binding+P450 medited
N-hydroxylation

LUMO䉣䊈䊦䉩䊷䈏ૐ䈇= ᳞ᩭ᡹᠄ฃ䈔䉇䈜䈇

LUMO(eV)ᑷᬐଈ⇈∅∙↝ᢡˡ൒ࣱ∇⇑⇱⇠∆..

⸘▚ᣇᴺ: HF/6-31G(d,p)

N
N

H2N

aryl nitrenium ion

1.80

O
HN

NdR

1.60

ί҄ӳཋ፭ὸ
1.40

HOMOࠛࡀ࡞ࠡ࡯
࡟ࡌ࡞߇ૐ޿㧩 ㉄ൻߐࠇߦߊ޿DNA߳૞↪ߔࠆ෻ᔕᵴᕈ⒳ߦߥࠅߦߊ޿

1.20

1.00

ᵟᶋᶃᶑᚾ᬴ᵆኬᓏửဇẟỦ‫ီ٭‬Ҿࣱᚾ᬴ᵇᨏࣱࣱᨗ

LUMO(eV)

A
1.16

B
1.62

C
1.20

D
1.67

E
1.13

plasma stability1.4

85.2

1.4

71.5

0.2

F
1.60

53.4
̪37͠䇮3ᤨ㑆ᓟ䈱ᱷሽ₸37䇸㕖⥃ᐥ⹜㛎䋭䉧䉟䊄䊤䉟䊮䈻䈱ኻᔕ䈫ᣂ䈚䈇⹜䉂䋭䇹 200838‛ᕈ੍᷹ LogP

2䋩ක⮎R&D䊒䊨䉶䉴䈱⚫੺䋨᭎ⷐ䋩

•

HOMO-LUMO䉩䊞䉾䊒䈲శᲥᕈ䈱ᜰᮡ䈫䉅䈭䈦䈩䈇䉎

LogP 䋨᳓/䉥䉪䉺䊉䊷䊦ಽ㈩ଥᢙ䋩
LogP log 10 PP[Compound]octanol[Compound]water‛⾰䈱ⷫ᳓ᕈ䊶⇹᳓ᕈ䈮㑐䈜䉎ၮ␆⊛䈭ᢙ୯ๆ෼₸䋨⤑ㅘㆊᕈ䋩
Bioavailability䋨BA: ↢‛ቇ⊛೑↪⢻䋩– ታ㛎䈪ᄙ䈒䈱ಽሶ䈱LogP䉕᳞䉄䉎䈱䈲࿎㔍•

੍᷹ᣇᴺ– ClogP䋨ਛᕈ䈱⁁ᘒ䉕⸘▚䋩– ACD/LogD䋨䉟䉥䊮ൻ⁁ᘒ䉅⠨ᘦ䈚䈩⸘▚䋩•ㇱಽ᭴ㅧ䋨䊐䊤䉫䊜䊮䊃䋩䈱logP䈱✚๺

LogP¦a f  ¦b Fi ii 1, Njjj 1, Mf : fragment values, F : interaction factors– ታ᷹୯䈎䉌૞ᚑ䈚䈢䊐䊤䉫䊜䊮䊃䈱䊤䉟䊑䊤䊥– 䊐䊤䉫䊜䊮䊃䈏䊤䉟䊑䊤䊥䈮ή䈇႐ว䈮䈲䇮⚿วᖱႎ䈭䈬䈎䉌䊐䊤䉫䊜䊮䊃䈱logP䉕ផቯ– ಽሶౝ᳓⚛⚿ว䉕⠨ᘦ

䋼ClogP䈱⸘▚଀䋾Brฦ䊐䊤䉫䊜䊮䊃䈱ነਈ

ValueBromide [aromatic]
6 aromatic isolating carbons
5 hydrogens on isolating carbons

1.090
0.780
1.135

ClogP=ഃ⮎䈮䈍䈔䉎
Exa computing 䈻䈱ᦼᓙ3.005

䋼ACD/LogD䋾
LogD log 10 D⸃㔌䉕⠨ᘦ䈚䈩▚಴
AHA- 䋫H+D[AH]octanol  [A - ]octanol[AH]water  [A - ]water

ACD/LogD, Advanced Chemistry Development, Inc., Toronto ON, Canada, www.acdlabs.com
39䌩㫅㩷㪪㫀㫃㫀㪺㫆 㪟㪫㪪㩷㩽㩷㪦㫇㫋㫀㫄㫀㫑㪸㫋㫀㫆㫅㩷㩿᭎ᔨ࿑㪀Ⱞ⊕⾰404䋩ഃ⮎䈮䈍䈔䉎Exa computing䈻䈱ᦼᓙRNaseT1 & 2’-GMP䈱ળวㆊ⒟1ᧄ㎮RNA䈱GႮၮ䈱3’૏
䊥䊮㉄⚿ว䈱ട᳓ಽ⸃㉂⚛

ಽሶળว⚿วㇱ૏ត⚝2’-GMP(105 /ᣣ)⿥㜞ㅦ䍘䍻䍩䍽䍋䍎䍞࠼࠶ࠠࡦࠣ

Free Energy Surface(1 /ᣣ)

RNaseT1 䋨104Res䋫Na+) : -4ଔ
2’-GMP : -2ଔ

(10 /ᣣ)(1 /ᣣ)

䊥䊷䊄ᦨㆡൻઍ⻢‛੍᷹⚿ว⥄↱ࠛࡀ࡞ࠡ࡯ӠӠ)(䋱ᣣ䈪⸘▚䈚䈢䈇ಽሶᢙ)4142

䉺䊮䊌䉪⾰䋭㒖ኂ೷㑆䈱᳓ಽሶ㈩ะ

㪉㪇

䋺2’GMP㪈㪇䋺⍫ශ䈱ะ䈐䈲䇮᳓䈱㈩ะ

ITC᷹ቯ⚿ᨐ䌛⥄↱䍒䍦䍷䍕䍼䍎䋨ӠG䋩 ,䍒䍻䍞䍷䍩䍽䍎(ӠH),䍒䍻䍢䍹䍩䍽䍎䋨-TӠS䋩䌝
N

㪊㪇

㪄㪈㪇

RNaseT1NH
N
N

N

N

NH

O

Compd.1
IC50=2800nM

㪇HNNNHFFF

㪈㪇㪱㩷㪘㫏㫀㫊
㪊㪇

NNONNHN㪉㪇㪄㪊㪇

HOHONN㫋㪔㪋㪅㪇㫅㫊
1500ps

OON

㪇

㪄㪉㪇

ONHOFF
F

Compd.2
IC50=27nM

㪋㪅㪇Compd.3
IC50=6.4nM㼺㪞㪄㪈㪇㼺㪟㪄㪫㼺㪪㪉㪅㪇

4000ps㫋㪔㪍㪅㪇㫅㫊㪄㪉㪇㪉㪇㪇㪅㪇㪄㪊㪇㪈㪇㪄㪊㪇㪱㩷 㫏㫀㫊4䋩ഃ⮎䈮䈍䈔䉎Exa computing䈻䈱ᦼᓙ㪄㪉㪇㪄㪈㪇

㪇㪈㪇㪉㪇㫂㪺㪸㫃㪆㫄㫆㫃㪱㩷㪘㫏㫀㫊4䋩ഃ⮎䈮䈍䈔䉎Exa computing䈻䈱ᦼᓙ㪊㪇 㫋㪔㪉㪅㪇㫅㫊
500ps

㪊㪇

㪯㩷㪘㫏㫀㫊㪇㪄㪉㪅㪇㪄㪋㪅㪇㪄㪍㪅㪇

㪄㪈㪇

㪄㪏㪅㪇
㪄㪉㪇

㪄㪈㪇㪅㪇

㪄㪊㪇

㪄㪈㪉㪅㪇

434䋩ഃ⮎䈮䈍䈔䉎Exa computing䈻䈱ᦼᓙ㪚㫆㫄㫇㫆㫌㫅㪻㩷㪉Compd.2

㪚㫆㫄㫇㫆㫌㫅㪻㩷㪊Compd.3444䋩ഃ⮎䈮䈍䈔䉎Exa computing䈻䈱ᦼᓙ⤑ㅘㆊᕈ䋨ฃേ᜛ᢔ䋩⢄ઍ⻢㉂⚛䋺CYP䈮䉋䉎⮎‛ઍ⻢‛੍᷹⤑ㅘㆊ⥄↱䉣䊈䊦䉩䊷䊒䊨䊐䉜䉟䊦

Human Cytochrome P450s

CYP3A4㪚㫆㫄㫇㫆㫌㫅㪻㩷㪈Compd.1

18 family
58 gene1ൻว‛䋺 10ns㬍25point=500nsᦨᄢᱷၮᢙ:543
ᦨዊᱷၮᢙ:434
ᐔဋ䋺505⃻࿷ProteinDF
F.Sato et al., Phys.Chem.Lett.341,645(2001)

Heme

ABINIT-MP዁᧪

T.Nakano et al., Phys.Chem.Lett. 318,614(2000)⃻࿷⸘▚ᤨ㑆䋺250ᣣ
䋨MDEngine䋺0.2TFLOPS)⸘▚ᤨ㑆䋺5⑽䋨Exa computer䋺1EFLOPS䈫䈜䉎䋩⸘▚ᤨ㑆䋺103ᐕ䌾105ᐕ
䋨PC䍖䍵䍛䍞䋺100GFLOPS䋩዁᧪⸘▚ᤨ㑆䋺䌾1ㅳ㑆䋨Exa computer䋺1EFLOPS䈫䈜䉎䋩઀੐
Tieleman et al.,Biophys. J. 85 3475 (2003)

454䋩ഃ⮎䈮䈍䈔䉎Exa computing䈻䈱ᦼᓙ4䋩ഃ⮎䈮䈍䈔䉎Exa computing䈻䈱ᦼᓙFree Energy Surface ⸃ᨆ⃻࿷46⸘▚ᤨ㑆䋪䈱⷗Ⓧ(᭎᭎▚)⚿วㇱ૏ 㪝㫉㪼㪼㩷㪜㫅㪼㫉㪾㫐㩷 ⤑ㅘㆊ㪪㫌㫉㪽㪸㪺㪼ត⚝䋨㪤㪛㪀䋨㪤㪛㪀䋨䌍䌏㪆䌍䌄䋩㪈㩷㪚㫆㫄㫇㪻㩷䋯 ᐕ⚻㛎⊛⋧੕૞↪㑐ᢙ⃻࿷዁᧪ 䋨Exa(1018)Computer <䋩
1 Compd / ᢙᣣ㪸㪹㩷㫀㫅㫀㫋㫀㫆㩷⋧੕૞↪㑐ᢙ㪜㫏㪸䉮䊮䋱䋰ᣣ䌾䋱䋰㪍ᐕ䋲䋵䋰ᣣ㪚㪰㪧㪑ઍ⻢‛੍᷹䋨㪤㪦㪀䌾䋱䋰㪌ᐕ䌍䌄ኾ↪ᯏ䌐䌃䉪䊤䉴䉺䌍䌄ኾ↪ᯏ䌐䌃䉪䊤䉴䉺㪇㪅㪇㪍⑽䌾㪈䊱᦬㪌⑽䌾㪈ㅳ㑆䋪Exa䉮䊮䈱ᕈ⢻䉕ᒁ䈐಴䈜(⿥ਗ೉)䊒䊨䉫䊤䊛䈏㐿⊒䈪䈐䈢႐ว䇯
MDኾ↪ᯏ䋺ᄢᱜ⵾⮎㐿⊒䋨ታലᕈ⢻䋲䋰䋰GFLOPS)
47

48

2䋩ක⮎R&D䊒䊨䉶䉴䈱⚫੺䋨᭎ⷐ䋩ഃ⮎䊒䊤䉾䊃䊖䊷䊛

䌾1ᐕᮡ⊛ಽሶ
䈱․ቯ

䌈䌔䌓↢‛ᵴᕈ䋺䊶⚿วታ㛎䍛䍖䍶䍎䍤䍻䍖䍼♽䈱᭴▽1䌾2ᐕ䍶䍎䍢䍼ൻว‛ត ⚝⮎ ല䋺䊶㫀㫅㩷㫍㫀㫋㫉㫆㩷⮎ല⹜㛎૕ౝേᘒ䋺*ⴊẏਛ቟ቯᕈ䊶ๆ෼ᕈ䋨⤑ㅘㆊᕈ䋩㪁㩷䍩䍢⢄䊚䉪䊨䉸䊷䊛ઍ⻢቟ቯᕈ㪁㩷㪚㫐㫇㒖ኂ䋨ᢙಽሶ⒳䋩㪁㩷෻ᔕᕈઍ⻢‛䋨㪞㪪㪟䍢䍵䍍䍩䍽䍻䍖䍼䍏䍍䍜䍐䋩቟ ో ᕈ䋺䊶ㆮવᲥᕈ㩿◲ᤃဳ㪘㫄㪼㫊㪀㪁㩷ᔃⴊ▤♽Ქᕈ䋨hERG䍟䍊䍦䍷⚿ว䋩‛ ᕈ䋺䊶⚐ᐲ䇮ṁ⸃ᐲ㩿᳓㪀䇮ಽ㈩ଥᢙ䇮䊶 䋳䌄᭴ㅧ੍᷹䋨ૐಽሶ䇮Ⱞ⊕⾰䋩
䊶 ㊀䈰ว䉒䈞䇮䍪䍅䍎䍭䍘䍪䍉䍏䈱᛽಴䊶 䍪䍅䍎䍭䍘䍪䍉䍏䍛䍖䍶䍎䍤䍻䍖䍼䊶 ⶄว૕⚿ว᭽ᑼ੍᷹

1䌾3ᐕ1ᐕൻ ว ‛ᦨ ㆡ ൻൻว‛䈱⛉䉍ㄟ䉂䍶䍎䍢䍼ൻว‛ഃ ಴⮎ ല䋺䊶㫀㫅㩷㫍㫀㫋㫉㫆㩷㩽㩷㫀㫅㩷㫍㫀㫍㫆⮎ല㩿㪧㪦㪚㪀⹜㛎૕ౝേᘒ䋺㪁ⴊẏਛ቟ቯᕈ䊶ๆ෼ᕈ䋨⤑ㅘㆊᕈ䋩㪁㩷䍩䍢⢄䊚䉪䊨䉸䊷䊛ઍ⻢቟ቯᕈ㪁㩷㪚㫐㫇㒖ኂ䋨฽ ෻ᔕᕈઍ⻢‛䋩㪁㩷෻ᔕᕈઍ⻢‛䋨㪞㪪㪟䍢䍵䍍䍩䍽䍻䍖䍼䍏䍍䍜䍐䋩㪁㩷䍏䍷䍪䍼䍮䍻䈫䈱⚿ว₸䋨䍩䍢䇮േ‛䋩㪁㩷㪧♧䍞䍻䍨䍽䍖⾰㑐ਈ䈱᦭ή቟ ో ᕈ䋺䊶ㆮવᲥᕈ㩿㪘㫄㪼㫊䇮䍭䍑䍛䍶䍻䍪䍉䍎䍭㪀㪁㩷ᔃⴊ▤♽Ქᕈ 䋨hERG㔚ᵹ䋬㪿㪜㪩㪞㪃㩷㪥㪸㪂䋬㪚㪸㪉㪂䍟䍊䍦䍷⚿ว䋩䊶৻⥸Ქᕈ䋨න࿁䋩‛ ᕈ䋺䊶⚐ᐲ䇮ṁ⸃ᐲ㩿᳓㪀䇮ಽ㈩ଥᢙ䇮䊶 ⶄว૕⚿ว᭽ᑼ੍᷹䋨⥄␠䌇䌁䋩䊶 ⚿ว⥄↱䍒䍦䍷䍕䍼䍎⸘▚㩿㪤㪤㪄㪧㪙㪪㪘㪀䊶 ಽሶ㑆⋧੕૞↪⸃ᨆ㩿㪝㪤㪦㪀䊶 ಽ㈩ଥᢙ䇮ṁ⸃ᐲ䇮Ქᕈ੍᷹⮎ല䋺䊶㫀㫅㩷㫍㫀㫋㫉㫆䇮㫀㫅㩷㫍㫀㫍㫆⮎ല૕ౝേᘒ䋺䊶Cyp㒖ኂ䈱♖ᩏ䋨 ᢙಽሶ⒳䋩
䊶䍩䍢⢄ઍ⻢㉂⚛⺃ዉ䊶䍵䍫䍼䍷૕䉕↪䈇䈢૕ౝേᘒ⹜㛎䋨ๆ෼䋺ⴊਛ᡼኿⢻Ớᐲ䇮ⴊਛᧂᄌൻ૕/ᵴᕈ૕Ớᐲ䋩䊶ਥઍ⻢‛䈱หቯ䋨in vitroઍ⻢‛䉕฽䉃䋩䊶䍵䍫䍼䍷૕䉕↪䈇䈢෻ᔕᕈઍ⻢‛䈱⏕⹺䊶ಽᏓ䋨⚵❱ਛỚᐲ䇮Ⱞ⊕⚿ว/ⴊ⃿⒖ⴕ䋩䊶ឃᴭ䋨ዩਛ䊶⢙᳝ਛឃᴭ䋩䊶㕖䈕䈦ᱤ㘃PK⹜㛎䊶TKᧄ⹜㛎䋨GLP䋩↪᷹ቯᴺ䈱䍨䍼䍶䍡䍼䍎䍚䍌䍻቟ోᕈ䋨㕖䌇䌌䌐䋩䋺䊶෻ᓳᛩਈᲥᕈ⹜㛎䋨䍵䍍䍢/ᄢേ‛䋩䊶ㆮવᲥᕈ⹜㛎䋨Ames䇮ᨴ⦡૕⇣Ᏹ)䊶቟ోᕈ⮎ℂ䋨ਛᨔ␹⚻♽䇮ᔃⴊ▤♽䇮๭ๆ♽䋩⿒ሼ: ዁᧪⊛䈮ಽሶ䉲䊚䊠䊧䊷䉲䊢䊮น⢻㗄⋡49

Exa Computingᓟ䈱ഃ⮎䈱ᆫ䋨᭎ᔨ࿑䋩

⮎ℂ

⮎ℂ

቟ోᕈ

቟ోᕈ᦭ᯏวᚑ

⸘▚‛ℂ⮎‛േᘒ⮎‛േᘒTeraPeta

Exa50