1995 Fiscal Year Final Research Report Summary
Development of New Methoda for Lead Discovery Using Computer
| Project/Area Number |
06557133
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| Research Category |
Grant-in-Aid for Developmental Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
医薬分子機能学
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| Research Institution | The Kitasato Institute (1995)
The University of Tokyo (1994) |
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Principal Investigator |
ITAI Akiko The Kitasato Institute, Center for Biological Function, Senior Research Scientist, 生物機能研究所, 部長研究員 (60012647)
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| Co-Investigator(Kenkyū-buntansha) |
TOMIOKA Nobuo The Kitasato Institute, Center for biological Function, Research Scientist, 生物機能研究所, 研究員 (20202202)
ENDO Yasuyuki University of Tokyo, Faculty of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (80126002)
IWAI Yuzuru The Kitasato Institute, Center for Biological Function, Vice Director, 生物機能研究所, 副所長 (70099977)
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| Project Period (FY) |
1994 – 1995
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| Keywords | drug design / lead generation / drug lead / computer drug design / drug design software / de novo ligand design / 自動ドッキング |
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| Research Abstract |
We have long been developing new methods for rational drug design using computer. With a remarkable progress in techniques of protein crystallography, 3D structures of many proteins or protein-ligand complexes, which have important biological functions, have been elucidated or are being elucidated. Structural information of the target receptor is most useful for designing new ligands with quite different structures as well as for interpreting structure-activity relations. In this research project, we have developed methods for de novo ligand design for drug lead discovery. One of them is a method for searching 3D-structure databases of existing compounds by receptor binding. Conformation-flexible search of 3D-databases was realized by making use of automatic docking method which we have developed previously. Hit compounds can be obtained and assayd without syntheses, if databases of available compounds are searched. The usefulness of the method was confirmed by the application to several enzyme systems. In dihydrofolate reductase, all the known inhibitors in the database were included in the 'hits'. In the HIV protease system, more than ten compounds showed significant inhibitory activity among fifty compounds of 'hits'. The highest potency was 20muM (Ki).
Furthermore, we have developed a new method which provides both advantages of structure construction method and database search method. In this method structures analogous to the ligand structures output from the structure construction method are very rapidly searched from 2D-databases by topological search. The advantage of structure construction method is that ligand structure which can well fit to the receptor cavity can be output regardless the structure is existing or nonexisting. By this new method, analogous hit compounds available can be assayd instead of synthesizing compounds with output structures themselves.
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Research Products
(10 results)
