Evolutionary insights into the control of drug specificity

Fernandez, Ariel

Title:

Evolutionary insights into the control of drug specificity

dc.contributor.author	Fernandez, Ariel
dc.contributor.corporatename	Rice University
dc.date.accessioned	2010-12-02T20:48:16Z
dc.date.available	2010-12-02T20:48:16Z
dc.date.issued	2010-11-10
dc.description	Ariel Fernandez, Karl F. Hasselmann Professor of Bioengineering at Rice University, presented a lecture on Wednesday, November 10, 2010 from 11:30 AM to 1:00 PM in the Klaus Advanced Computing Building (Klaus), Room 1116E on the Georgia Tech campus.	en_US
dc.description	Runtime: 73:22 minutes	en_US
dc.description.abstract	We shall present on research endeavors focusing on controlling specificity in molecularly targeted anticancer therapy. A basic goal is to reduce toxic side effects by structure-based drug design exploiting our understanding of the evolutionary basis of specificity. Emphasis will be placed on engineering kinase inhibitors (KIs) with minimal clinical uncertainty. A radical innovation is on its way in terms of rationally redesigning KIs to reduce their toxicity. As it turns out, we can control specificity to an unprecedented degree and hence decisively contribute to test the limits of therapeutic efficacy. To support this claim, we start by noting that cross reactivities of KIs arise because of the structural similarity and amino acid conservation across evolutionarily related (paralog) kinases. Yet, while paralogs share a similar structure, they are "wrapped" differently. As we compare the microenvironments of intramolecular hydrogen bonds aligned across paralog structures we notice crucial differences: some hydrogen bonds are exposed to solvent in one kinase and shielded from water in another, or, rather, one hydrogen bond may be deficiently wrapped in one kinase but well wrapped in another. Taking into account such local differences, we are able to redesign KIs because deficiently wrapped hydrogen bonds -the so-called dehydrons - not only distinguish paralogs but are also inherently sticky. Hence, a new design strategy to achieve higher specificity emerges as we turn KIs into exogenous wrappers of dehydrons that are not conserved across structures of common ancestry. Such wrapping designs enable paralog discrimination and hence yield drugs capable of curbing side effects.
dc.format.extent	73:22 minutes
dc.identifier.uri	http://hdl.handle.net/1853/36240
dc.language.iso	en_US	en_US
dc.publisher	Georgia Institute of Technology	en_US
dc.relation.ispartofseries	Distinguished Scientific Leader Lecture
dc.subject	Dehydron	en_US
dc.subject	Drug design	en_US
dc.subject	Specificity	en_US
dc.title	Evolutionary insights into the control of drug specificity	en_US
dc.type	Moving Image
dc.type.genre	Lecture
dspace.entity.type	Publication
local.contributor.corporatename	Integrative BioSystems Institute
local.relation.ispartofseries	Distinguished Scientific Leader Lecture
relation.isOrgUnitOfPublication	139564d0-ade3-4d4d-8bcc-c5cf8a364b21
relation.isSeriesOfPublication	98a4f688-dbb5-46b3-a9b6-7aa71d7e0ba0