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dc.contributor.advisorBruce Tidor.en_US
dc.contributor.authorRadhakrishnan, Mala Lakshmien_US
dc.contributor.otherMassachusetts Institute of Technology. Dept. of Chemistry.en_US
dc.date.accessioned2007-12-07T15:26:10Z
dc.date.available2007-12-07T15:26:10Z
dc.date.copyright2007en_US
dc.date.issued2007en_US
dc.identifier.urihttp://hdl.handle.net/1721.1/39674
dc.descriptionThesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2007.en_US
dc.descriptionThis electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.en_US
dc.descriptionIncludes bibliographical references.en_US
dc.description.abstractThis thesis addresses challenging aspects of drug design that require explicit consideration of more than a single drug-target interaction in an unchanging environment. In the first half, the common challenge of designing a molecule that recognizes a desired subset of target molecules amidst a large set of potential binding partners is explored. Using theoretical approaches and simulation of lattice-model molecules, relationships between binding specificity and molecular properties such as hydrophobicity, size, and conformational flexibility were achieved. Methods were developed to design molecules and molecular cocktails capable of recognizing multiple target variants, and some were integrated with existing methods to design drug cocktails that were predicted to inhibit seven variants of HIV-1 protease. In the second half of the thesis, computational modeling and designs that were used to understand how cytokine binding and trafficking events affect potency are described. A general cellular-level model was systematically explored to analyze how signaling and trafficking properties can help dictate a cytokine-receptor binding affinity appropriate for long-term potency.en_US
dc.description.abstract(cont.) To help create an accurate cellular-level model of signaling and trafficking for one system in particular, the erythropoietin (Epo) system, we computationally designed mutant erythropoietin receptor (EpoR) molecules for use as experimental probes. By mutating a residue predicted to contribute to pH-dependent Epo-EpoR binding, reagents were designed to facilitate study of endosomal binding and trafficking. Furthermore, a pair of mutant Epo receptors was designed to form a specific, heterodimeric complex with Epo to facilitate study of each individual EpoR's role in signaling via the asymmetric Epo-(EpoR)2 complex.en_US
dc.description.statementofresponsibilityby Mala Lakshmi Radhakrishnan.en_US
dc.format.extent353, [3] p.en_US
dc.language.isoengen_US
dc.publisherMassachusetts Institute of Technologyen_US
dc.rightsM.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.en_US
dc.rights.urihttp://dspace.mit.edu/handle/1721.1/7582
dc.subjectChemistry.en_US
dc.titleTackling the bigger picture in computational drug design : theory, methods, and application to HIV-1 protease and erythropoietin systemsen_US
dc.typeThesisen_US
dc.description.degreePh.D.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Dept. of Chemistry.en_US
dc.identifier.oclc181374294en_US


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