WEDNESDAY, JUNE 19

MORNING SHORT COURSE: 9:00 am - 12:00 pm*  

Structure-Based Drug Design for Epigenetic Targets

Epigenetic processes are the focus of intense interest, and the families of proteins that mediate epigenetic signalling are a highly promising source of new drug targets.  Tackling this emerging field of novel drug targets is not without its challenges.  This workshop will review the contribution that structural biology has made to the discovery of small molecule modulators.  Structural information can be invaluable in determining the druggability of potential targets, and in enabling more efficient identification of hit molecules.  Structural information can also guide the design of compounds with improved affinity for the target, or selectivity versus other targets.  This introductory course on drug design for epigenetic targets will focus especially on emerging targets such as bromodomain (readers), methyltransferase (writers) and lysine demethylase (erasers).


Johnathan R. Whetstine, Ph.D., Assistant Professor of Medicine, Harvard Medical School
Philip Fallon, Ph.D., Senior Medicinal Chemist, Domainex Ltd. 

STRUCTURE-BASED DRUG DESIGN FOR KINASE 

1:15 pm Chairperson’s Opening Remarks

Adam C. Palmer, Ph.D., Postdoctoral Fellow, Department of Systems Biology, Harvard Medical School(1) the special role that structure-based drug design can play in treating drug resistant infectious diseases
(2) how considering the evolution of resistance during drug development could produce drugs with more long-lasting clinical efficacy
(3) how drug resistance can be used as a tool to understand mechanism of drug action
 

1:20 Structure-Based Design of Potent and Selective Inhibitors of PI3-Kinase Delta

Jeremy M. Murray, Ph.D., Scientist, Structural Biology, Genentech

Inhibition of PI3Kδ is considered to be an attractive mechanism for the treatment of inflammatory diseases and leukocyte malignancies. Using a structure-based design approach, we have identified a series of potent and selective inhibitors of PI3Kδ. These inhibitors do not occupy the induced selectivity pocket between Trp760 and Met752 that is observed for other families of selective PI3Kδ inhibitors. Instead, the selectivity of the compounds for inhibition of PI3Kδ relative to other PI3K isoforms appears to be due primarily to the strong interactions these inhibitors are able to make with Trp760 in the PI3Kδ binding pocket. This talk will discuss the structural understanding of the selectivity of these inhibitors against other isoforms, pharmacokinetic properties and the ability of select compounds to inhibit the function of B-cells in vivo.

1:50 MD Simulations of Mutant and WT PI3Kα: Insights into the Mechanism of Overactivation and Implications for Drug Design

Zoe Cournia, Ph.D., Investigator, Biomedical Research Foundation, Academy of Athens

PI 3 kinase alpha (PI3Kα) is one of the most frequently mutated proteins in human cancers. Molecular dynamics simulations in aqueous solution performed for wild type (WT) and H1047R mutant PI3Kα proteins, revealed different dynamical and structural features for the two proteins, which may lead to kinase overactivation in the mutant variant. Binding site prediction and virtual screening further facilitated the development of novel mutant-specific PI3Kα inhibitors that exploit the altered conformation of the mutant with respect to the WT protein.

DRUG RESISTANCE 

2:20 Guiding the Design of Robust Inhibitors Targeting HIV and HCV Proteases by Using the Dynamic Substrate Envelope

Aysegul Ozen, Ph.D. Candidate, Biochemistry & Molecular Pharmacology, University of Massachusetts Medical School

Drug resistance is a major concern in the treatment of quickly evolving diseases. At the molecular level, drug resistance reflects a subtle change in the balance of molecular recognition by the target enzyme due to mutations in favor of substrate processing versus inhibitor binding. Robust inhibitors can be designed by mimicking the binding features of the natural substrates to minimize the chances of resistance. 

2:50 Refreshment Break in the Exhibit Hall with Poster Viewing

3:30 Towards a New Generation of Animicrobial Antifolates

Dennis L. Wright, Ph.D., Professor of Pharmaceutical Sciences and Chemistry, University of Connecticut

We are using a structure-based design approach to develop potent and selective inhibitors of the enzyme dihydrofolate reductase (DHFR) from a variety of pathogenic organisms. Analysis of crystal structures of trimethoprim-resistant and naturally-insensitive enzymes led to the design of a series of propargyl-linked antifolates characterized by high potency, good selectivity over the human form of the enzyme and good anti-microbial activity.

4:00 Understanding Drug Mechanism of Action by Target Gene Overexpression

Adam C. Palmer, Ph.D., Postdoctoral Fellow, Department of Systems Biology, Harvard Medical School

The molecular targets of drugs can sometimes, but not always, be identified amongst genes that confer drug resistance when overexpressed. We quantitatively overexpressed genes encoding known antibiotic targets and observed that drug resistance does not only increase; it can remain unchanged, decrease, or even have a non-monotonic dependence on target expression. These diverse effects are explained by simple models considering gene toxicity and drug-induction of harmful target-catalyzed reactions. The relation between drug resistance and target expression may reveal unexpectedly complex mechanisms of drug action.

4:30 Close of the Day

DINNER SHORT COURSE (JUNE 19, 6:00-8:00 PM)*  

*Separate registration required.

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