Abstract:
:Orientation of ten water molecules bound strongly at the contact surface of the dihydrofolate reductase-methotrexate enzyme-inhibitor complex was determined theoretically. To optimize the orientation of the water molecules, a recent method based on a simple electrostatic model was applied. The electrostatic complementarity in the binary complex was investigated using the lock-and-key model, considering the effect of the water molecules as well. The strongly bound water molecules improve the electrostatic fit in the pteridine region of methotrexate. Their role in the benzoic amide and gamma-glutamate region is to decrease the internal energy by creating water bridges among remote polar sites making it possible to form H-bonds. Some modifications in the inhibitor structure were proposed for achieving greater inhibitor potency. The presumably enhanced effect is ascribed to the free energy gain in repelling the water molecules from the contact surface to the bulk of the solvent, and, in other cases, to internal energy decreases due to better electrostatic fit in the enzyme-inhibitor complex.
journal_name
J Comput Aided Mol Desjournal_title
Journal of computer-aided molecular designauthors
Nagy Pdoi
10.1007/BF01532054subject
Has Abstractpub_date
1988-04-01 00:00:00pages
65-76issue
1eissn
0920-654Xissn
1573-4951journal_volume
2pub_type
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
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更新日期:2010-01-01 00:00:00
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
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更新日期:2009-08-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00134180
更新日期:1996-12-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
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更新日期:1996-08-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00129749
更新日期:1991-04-01 00:00:00
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
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更新日期:2009-01-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF01532991
更新日期:1989-01-01 00:00:00
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journal_title:Journal of computer-aided molecular design
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更新日期:2020-10-26 00:00:00
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journal_title:Journal of computer-aided molecular design
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doi:10.1007/s10822-018-0182-2
更新日期:2019-02-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1025386326946
更新日期:2003-02-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-017-0038-1
更新日期:2017-08-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-008-9187-6
更新日期:2008-05-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-006-9038-2
更新日期:2006-02-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
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更新日期:2007-12-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1007969526447
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-015-9887-7
更新日期:2016-01-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/b:jcam.0000035200.30340.41
更新日期:2004-03-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-017-0053-2
更新日期:2018-01-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-005-7928-3
更新日期:2005-06-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/b:jcam.0000005754.24588.a0
更新日期:2003-09-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00355046
更新日期:1996-06-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1008111820916
更新日期:2000-05-01 00:00:00
abstract::The pharmacophoric concept plays an important role in ligand-based drug design methods to describe the similarity and diversity of molecules, and could also be exploited as a molecular representation scheme. A three-point pharmacophore method was used as a molecular representation perception. This procedure was implem...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-007-9110-6
更新日期:2007-05-01 00:00:00
abstract::Estimation of bioavailability and toxicity at the very beginning of the drug development process is one of the big challenges in drug discovery. Most of the processes involved in ADME are driven by rather unspecific interactions between drugs and biological macromolecules. Within the past decade, drug transport pumps ...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1023828527638
更新日期:2002-11-01 00:00:00