Abstract:
:Much has been discussed about the proper physicochemical properties (e.g., molecular weight, hydrophobicity, etc.) that should be considered when utilizing fragment leads in drug design. However, little has been reported as to what emphasis, if any, should be placed on the potency of the resulting fragment leads. In this report, a retrospective analysis of 18 highly optimized inhibitors is described in which the compounds were systematically deconstructed until the minimal binding elements could be identified. An analysis of the potency changes that were observed as the leads were reduced in size indicate that a nearly linear relationship exists between molecular weight and binding affinity over the entire range of sizes and potencies represented in the dataset. On the basis of these observations, prediction maps can be constructed that enable critical and quantitative assessments of the process of lead identification and optimization. These data place well-defined limits on the ideal size and potency of fragment leads that are being considered for use in fragment-based drug design.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Hajduk PJdoi
10.1021/jm060511hsubject
Has Abstractpub_date
2006-11-30 00:00:00pages
6972-6issue
24eissn
0022-2623issn
1520-4804journal_volume
49pub_type
杂志文章abstract::Several 4-benzyl analogues of 5-ethyl-6-methyl-4-(phenylthio)pyridin-2(1H)-ones were synthesized and evaluated for their anti-HIV-l activities. Key transformations include metalation at the 4-C-position of 5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine (5) and its coupling with benzyl bromide or benzaldehyde deriv...
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pub_type: 评论,杂志文章
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更新日期:2010-12-23 00:00:00
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更新日期:2007-06-14 00:00:00
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