Wednesday, June 6
11:45 AM Conference Registration
1:15 PM Chairperson’s RemarksChris Williams, Ph.D., Principal Scientist, Chemical Computing Group
1:20 Integrate Structural, Biophysical and Computational Methods to Understand Glucokinase Function and Design Novel Allosteric Activators
Xiayang Qiu, Ph.D., Senior Director, Head of Structure Biology & Biophysics, Pfizer, Inc.
Despite the rapid advances in protein crystallography over the last two decades, SBDD successes still rely mostly on the intuitions of our scientists due to the lack of reliable computational tools to predict affinity, kinetics, thermodynamics, solvation and conformational dynamics. Through glucokinase and other examples, I will present our progresses in integrating diverse biophysical methods to strengthen the link between structure and function, and advocate for the development of predictive computational algorithms through expanded experimental datasets.
1:50 1:50 Structure-Guided Design of Biologically Active and Highly Selective Inhibitors of CK1-ð Protein Kinase
Scot Mente, Ph.D., Senior Research Scientist, Neuroscience Chemistry, Pfizer
Structure-guided design of biologically active and highly selective inhibitors of CK1-ð protein kinase for the treatment of neurological disorders. The CK1 family of protein kinases consists of seven moderately conserved isoforms in humans. This talk will highlight efforts aimed at finding potent and selective ligands for the CK1-d isoform as a circadian rhythm modifying agent.
2:20 Rational Approaches to Improving Selectivity in Drug DesignWoody Sherman, Ph.D., Vice President, Applications Science, Schrodinger, Inc.Optimizing binding selectivity is a key part of drug discovery. We present a survey of rational, structure-based approaches to selectivity design. We highlight the difference between broad and narrow selectivity and provide examples of how selectivity can be achieved using different molecular mechanisms.
2:50 Refreshment Break in the Exhibit Hall with Poster Viewing
3:30 Identification of DYG-out Inhibitors of LRRK2 Based on Structural Modeling and Enzyme Kinetic Studies
Min Liu, Ph.D., Assistant Director, The Laboratory of Drug Discovery for Neurodegeneration, LDDN, Harvard NeuroDiscovery Center, HNDC, Brigham and Women’s Hospital
Leucine-rich repeat kinase2 (LRRK2), a large and complex protein that possesses two enzymatic properties, kinase and GTPase, is one of the major genetic factors in Parkinson’s disease (PD). Over 40 mutations in LRRK2 have been found in the most common familial forms and some sporadic forms of PD, and have been associated with typical idiopathic, late-onset PD. Here we report the identification of DYG-out inhibitors of LRRK2 based on the combined structural modeling and enzyme kinetic studies.
4:00 Determining the Crystal Structures of Allosteric Kinase Inhibitor Complexes
Barbara Brandhuber, Ph.D., Director, Early Drug Discovery, Biology, Array BioPharma
Upon discovery of a kinase inhibitor that does not appear to bind in the ATP-binding cleft, structural biologists are challenged to determine the crystal structure of the inhibitor-bound kinase to enable structure-based drug design. Frequently, the inhibitor does not crystallize with a canonical kinase construct and therefore a new crystallographic effort is launched. In this presentation, several biochemical, biophysical, and bioinformatic approaches will be discussed which enable and complement crystallographic studies. The use of multi-disciplinary approaches to crystallographically determine the unique binding mode of an allosteric inhibitor interacting with both the regulatory pleckstrin-homology and kinase domains of AKT-1 will be described.
4:30 In silico Lead Finding through Holistic Understanding of Screening Data from Multiple Approaches
Meir Glick, Ph.D., Head, Lead Discovery Informatics, Novartis Institutes for BioMedical Research, Inc.
Understanding of biochemical, biophysical, pathway and functional information is critical for decision making and hypothesis generation in drug discovery. We will discuss the in silico approaches to support this challenge. For example, design of bio-diverse compound libraries and intentional targeting of a specific phenotype. Next, we will describe how the data should be mined and visualized to enable understanding of the molecular mechanism of action and prioritize the right chemical matter for a chemistry program.
5:00 End of Day
6:00-8:00 pm Dinner Short Course*
First Principles in Binding Kinetics: Towards Predicting Structure-Kinetics Relationships
David Swinney, Ph.D., CEO, Institute for Rare and Neglected Diseases Drug Discovery (iRND3)
Xavier Barril, Ph.D., ICREA Research Professor, Physical Chemistry Department, University of Barcelona
This course will address the questions on “why should I care about kinetics?” and “how can I understand and predict Structure-Kinetics relationships?” We will first review the role of binding kinetics in drug action and then focus on the particular case of protein-ligand non-covalent complexes, reviewing what is known so far about the structural determinants of binding kinetics. This course will help you with a better understanding and increased awareness of current state of the chemistry and pharmacology of binding kinetics.
*Separate Registration Required