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Date: Thursday, Aug 19, 2010
Time: 12:00 p.m. - 1:00 p.m. EST
Conformational Variant Profiling and Drug Discovery Strategies.
Presenter: Matt Kuruc - President
Outcomes of clinical trials are routinely plagued with problems associated with drug promiscuity and non-specific toxicity. To overcome these problems, targeting conformational variants has been a long sought after goal of drug development. Small molecule allosteric modulators may yet prove to be a viable strategy and efforts to structurally determine regulatory sites for modulation are increasing; recombinant mutagenesis for example, can model homogeneous conformational variants. Nevertheless for drug screening purposes, a critical deficiency still remains - industrial methods for broadly identifying and characterizing the kinetics of conformational variants that are responsible for the disease phenotype. Target enzymes of a drug can display a range of kinetic states – dictated by their various conformations (PTMs, natural transient features, and splice variants). Therefore a comparison of functional profiles generated from the intact protein conformations, are necessary to first establish conformational variant to disease correlations. Other drug discovery platforms consider either structural binding analysis by way of crystallography, or the relative expression and PTMs of protein families. However neither of these platforms can directly determine the kinetic contributions of the conformational variants.
In this webinar, ProFACT describes advances in its proprietary functional proteomics platform – SeraFILE™, and related Conformerics™ prospecting strategies, for all of these purposes. With this new technology platform, disease-associated variants can be compartmentalized, and enriched for purposes of screening and comparing small molecule modulation – a direct link to screening for new drug candidates. In some cases, such compartmentalized sub-proteomes will contain a heterogeneous mix of enzymes that will allow for a much greater characterization of steady-state, non-steady-state, and competitive affects of small molecule modulation, compared to current efforts that rely on homogeneous enzyme screening. As a result, conformational kinetic-based selectivity profiling should be more pharmaco-dynamically relevant and potentially provide new drug candidates with a higher therapeutic index.
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