College of Liberal Arts & Sciences

What Does Evolution Tell Us About Drug Discovery?

Feb 20, Wed 2007
1:30 pm, MRB 200 Conference Room

Dr. Phillip Bourne

Department of Pharmacology, University of California, San Diego

We have recently used protein structure to study evolution. An advantage of using structure is that we can see relationships over long evolutionary time scales that can not be observed by sequence alone. These studies point to relationships across gene families where only similarity in the functional sites remains [1]. We have begun to use these relationships to identify potential off-target binding sites for major pharmaceuticals. Finding such sites might explain a possible side effect of a drug or lead to the repositioning of a drug to treat a completely different condition. Examples of both situations will be discussed. First, we offer an explanation for side effects associated with Select Estrogen Receptor Modulators (SERMS), including tamoxifen [2] and second the repositioning of drugs used to treat Parkinson's disease as possible candidates in the treatment of extreme drug resistant tuberculosis.

[1] L. Xie and P.E. Bourne 2008 Detecting Evolutionary Linkages AcrossFold and Functional Space with Sequence Order Independent Profile-profile Alignments. PNAS, Accepted.

[2] L. Xie, J. Wang and P.E.Bourne 2007 In Silico Elucidation of the Molecular Mechanism Defining the Adverse Effect of Selective Esterogen Receptor Modulators. PLoS Comp. Biol., 3(11) e217.

[3] S. Kinnings, L. Xie and P.E. Bourne 2008 Repurposing Safe Pharmaceuticals to Treat Multi-drug and Extensively Drug Resistant Tuberculosis using an in silico Cross-gene-family Approach. In preparation.


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