Sangam: A Confluence of Knowledge Streams

Rational Approaches to Improving Selectivity in Drug Design

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dc.contributor Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory
dc.contributor Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
dc.contributor Whitehead Institute for Biomedical Research
dc.contributor Tidor, Bruce
dc.creator Huggins, David J.
dc.creator Sherman, Woody
dc.creator Tidor, Bruce
dc.date 2012-10-02T15:15:23Z
dc.date 2012-10-02T15:15:23Z
dc.date 2012-01
dc.date 2011-08
dc.date.accessioned 2023-03-01T18:11:24Z
dc.date.available 2023-03-01T18:11:24Z
dc.identifier 0022-2623
dc.identifier 1520-4804
dc.identifier http://hdl.handle.net/1721.1/73545
dc.identifier Huggins, David J., Woody Sherman, and Bruce Tidor. “Rational Approaches to Improving Selectivity in Drug Design.” Journal of Medicinal Chemistry 55.4 (2012): 1424–1444. Copyright © 2012 American Chemical Society
dc.identifier https://orcid.org/0000-0002-3320-3969
dc.identifier.uri http://localhost:8080/xmlui/handle/CUHPOERS/279089
dc.description Appropriate tuning of binding selectivity is a primary objective in the discovery and optimization of a compound on the path toward developing a drug. The environment in which drugs act is complex, with many potential interaction partners. Proteins, DNA, RNA, lipids, sugars, metabolites, and other small molecules all have the potential to interact with a drug, and in many cases these unexpected interactions lead to undesired and often severe side effects. Conversely, the ability to interact with multiple targets or drug resistance mutants can be advantageous in certain contexts. Designing a drug with the appropriate balance of avoidance of undesirable targets (narrow selectivity) and coverage of one or more targets of interest (broad selectivity, also referred to as promiscuity) is a continual drug development challenge. In many cases this objective is attained through trial and error, but there are rational approaches that can guide the tuning of selectivity, and examples have been published that illustrate a number of generalizable strategies. In this review, we discuss fundamental principles that account for selectivity and highlight examples where selectivity has been attained through rational design. An understanding of the general principles that drive selectivity should allow for more efficient design of compounds with desirable selectivity profiles.
dc.description National Institutes of Health (U.S.) (Grant GM082209)
dc.description National Institutes of Health (U.S.) (Grant GM065418)
dc.format application/pdf
dc.language en_US
dc.publisher American Chemical Society (ACS)
dc.relation http://dx.doi.org/10.1021/jm2010332
dc.relation Journal of Medicinal Chemistry
dc.rights Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
dc.source PubMed Central
dc.title Rational Approaches to Improving Selectivity in Drug Design
dc.type Article
dc.type http://purl.org/eprint/type/JournalArticle


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