Structure-Based Drug Design Conference Final Brochure.pdf

2:00 The Role of Recent Crystal Structures of Membrane
Bound Proteins in Drug Discovery for CNS Targets
Sid Topiol, Ph.D., CSO, Computational and Structural
Investigations, 3D-2Drug
I would present illustrations of the impact of recent X-ray
structure determinations for the more challenging CNS
targets, i.e., membrane bound proteins. For class C GPCR’s,
new opportunities for drug discovery are being identified
using X-ray structures of the extracellular regions. Other targets, such
as transporters and ion channels, are also now amenable to structurebased
drug design.
2:25 Hitting a Moving Target: Characterizing GPCR Signaling
through Long-timescale Molecular Dynamics Simulations
Ron Dror, Ph.D., Senior Research Scientist and Special
Advisor to the Chairman, D. E. Shaw Research
A mounting body of evidence indicates that drugs
induce GPCRs to interconvert between numerous
conformational states with distinct intracellular signaling
profiles. Recent advances in algorithms and hardware for
molecular dynamics (MD) simulations are now bringing the previously
inaccessible timescales on which these transitions occur within reach.
This talk will describe ongoing studies of GPCRs using state-of-the-art
MD simulations, which have provided a hitherto elusive glimpse of the
conformational dynamics underlying GPCR-mediated signaling by both
endogenous ligands and drugs.
2:50 Networking Refreshment Break
3:00 Beyond the Orthosteric Binding Site: A Structure-Based
SAR Analysis of the D3R Selective Compounds
Lei Shi, Ph.D., Assistant Professor, Department of Physiology
and Biophysics, HRH Prince Alwaleed Bin Talal Bin Abdulaziz
Alsaud Institute for Computational Biomedicine, Weill Cornell
Medical College
Selective targeting of dopamine D3 receptor (D3R) has
therapeutic implications in neuropsychiatric disorders and
drug additions. D3R selective compounds have two pharmacophores
and a connecting linker. The talk will highlight individual and combined
contributions of these components towards the selectivity in the
context of the D3R structure. A novel structure-based design scheme
to address specificity issues of highly homologous GPCRs will be
presented.
3:25 Moving in New Circles – Exploiting Macrocycles for Drug
Discovery
Nick Terrett, Ph.D., CSO, Ensemble Therapeutics Corp
Macrocycles are largely underexploited in drug discovery
because they are generally perceived as structurally
complex and difficult to access. Ensemble Therapeutics has
developed platforms for the rapid synthesis and screening
of macrocycles in order to identify leads for challenging
protein-protein interaction targets. The talk will focus on the design and
synthesis of macrocycle libraries and the successful discovery of novel
lead molecules with unprecedented activity and drug-like properties.
DRUG RESISTANCE
3:50 Strategizing to Develop Resistance-Proof Inhibitors
Bruce Tidor, Ph.D., Professor of Biological Engineering and
Computational Science, Massachusetts Institute of
Technology
The selection of resistant variants is an important problem
limiting the therapeutic usefulness of inhibitors to targets
undergoing rapid mutation, particularly for applications in
infectious disease and cancer. We report our work exploring general
strategies for the development of inhibitors that have a reduced
tendency to induce resistance, using HIV protease as a trial target.
4:15 Computational Approaches to Modeling the Emergence
of Drug Resistance
Ryan Lilien, M.D., Ph.D., Assistant Professor, Department of
Computer Science & Donnelly Centre for Cellular and
Biomolecular Research, University of Toronto
The emergence of drug resistance reduces the
effectiveness of many novel therapeutics. I will describe
computational methods for predicting resistance mutations
through their structural and functional effects on the protein target.
These methods may allow us to identify new ways to create drugs that
6
healthtech.com/SBD
are less likely to be made ineffective by pathogen evolution, understand
the key determinants of the evolution and spread of resistance, and
develop the ability to slow the emergence of resistant variants.
4:40 End of Conference