1991 Fiscal Year Final Research Report Summary
Development of computer system for generating drug structures based on drug-receptor interaction
| Project/Area Number |
01870094
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| Research Category |
Grant-in-Aid for Developmental Scientific Research
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| Allocation Type | Single-year Grants |
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| Research Field |
Chemical pharmacy
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| Research Institution | University of Tokyo |
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Principal Investigator |
ITAI Akiko University of Tokyo, Faculty of Pharmaceutical Sciences, 薬学部, 客員助教授 (60012647)
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| Co-Investigator(Kenkyū-buntansha) |
SHUDO Koichi University of Tokyo, Faculty of Pharmaceutical Sciences, 薬学部, 教授 (50012612)
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| Project Period (FY) |
1989 – 1991
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| Keywords | computer drug design / lead generation / protein structure / drug-receptor interaction / dihydrofolate reductase / morphine |
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| Research Abstract |
Although lead compound is very important for succeeding in drug development, it is so difficult to discoveror generate artificially without relying on chance. Then, we have developed two new methods and programs for generating possible ligand structures, which provide shapes and properties favorable for binding to the target receptor structures or receptor models. Among many such structures, we can synthsize a small number of structures which were selected and modified from the chemical and synthetic view point. One of them is a program, LEGEND, which construct molecules generating atoms one by one based on a force field and random numbers in the ligand binding region of the receptor. The program can generate structures which not only well fit to the receptor cavity but also form hydrogen bonds tothe receptor as many as possible. We have applied this program to an enzyme, dihydrofolate reductase(E. coli), whose 3Dstructure has been elucidated crystallographically. It was shown that generated structures were fairly stable intra- and intermolecularly and full of variety. A few of them are now under chemical syntheses, after iterative modification of the structure and computer simulation of the stability.
Another method is that based on the active structures of known ligand(drugs or natural bio-acitve compounds). The method construct automatically possible skeletal structures which maintain positions and orientations of functional groups presumed to be required for the biological activity. The program was applied to an analgesics, morphine, preserving the phenyl and nitrogen lonepair. The resulted structures included several new skeletal structures together with several known analgesics structures.
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