Profiling for ADME/Tox

8:00 Coffee

8:30 Chair’s Remarks

8:35 Issues of Computational Models for Predictive ADME
Dr. Terry Stouch, Head, Computational Chemistry, Lexicon Pharmaceuticals
The in silico modeling of biological properties of chemical entities has always been a challenging task. A principal challenge has always been the availability of a sufficient mass of data from which to draw reliable relationships between chemical structure and their biological effects. High-throughput profiling would appear to help solve this problem by providing a previously-unprecedented amount of data. However, depending on the desired endpoint of the in silico modeling, even this data must be treated with caution. Some of the issues and challenging of in silico modeling of profiling data will be discussed. The issue of the suitability for modeling of even high-quality data will be introduced.

9:05 Physicochemical Compound Profiling/PLS Analysis: Tools to Optimize In Vitro/MIC Activity of Acyl-Carrier Protein Synthase (AcpS) Inhibitors
Dr. Adam Gilbert, Principal Research Scientist, Exploratory Medicinal Chemistry, Wyeth Research
Physicochemical compound profiling measurements (aqueous solubility, PAMPA permeability and logD determinations) and PLS analysis of molecular quantitative structure-activity relationships were used to study several HTS hits that inhibit acyl-carrier protein synthase (AcpS), an essential enzyme in bacterial fatty acid biosynthesis. Using these tools, micromolar HTS hits without antibacterial MIC activity were quickly transformed into sub-micromolar chemical leads with antibacterial MIC activity in a several bacterial strains.

9:35 Biological, Chemical & Computational Fingerprints: Chemogenomic and Attrition Aspects
Dr. Jonathan S. Mason, Executive Director, Molecular Informatics Structure & Design, Pfizer Global R&D
The use of a variety of experimental and computational fingerprinting methods will be presented in the context of drug discovery. Novel approaches to cluster targets using chemical fingerprints and approaches to predict and orthogonalize attrition risk of drug candidates using biological profiling will be discussed.

10:05 Poster and Exhibit Viewing and Refreshment Break

10:45 TBA

11:15 Predictive Toxicogenomics for Compound Profiling

11:45 Panel Discussion

12:15 Lunch on your own
(Technology Workshop Sponsorship Available)

Drug-like and Lead-like Properties and Filters

1:45 Chair’s Remarks

1:50 Leads in Bioactivity Space: Are We Looking for the Appropriate Properties?
Dr. Tudor Oprea, University of New Mexico

2:20 How Do We Define Drug-Likeness and Lead-Likeness
Dr. Zhengming Chen, Principle Investigator, Computational, Combinatorial and Medicinal Chemistry, Purdue Pharma
Key points from recent studies on the topic of drug-likeness and lead-likeness will be presented. Several intriguing insights into the influence of molecular properties on the likelihood of progression through the drug development process and the trends in modern drug discovery will be given. The implications of the drug-likeness and lead-likeness studies results in our future design of screening library and selection of HTS hits for lead optimization will also be discussed.

2:50 Nonleadlikeness, Leadlikeness, and Target Class Tractability
Dr. Gilbert Rishton, Research Scientist, Small Molecule Drug Discovery and Neurobiology, Amgen, Inc.
Biochemical assays have largely supplanted functional biological assays as drug screening tools in the early stages of drug discovery. The de-selection of compounds that are “nonleadlike” binders (and bonders) and the proactive selection of those compounds that are “leadlike” in their binding to the target are vital components of the screening effort. The physiochemical properties of leadlikeness and the surprising differences between those properties and the now classical definitions of druglikeness are becoming apparent. The quality of our lead molecules and the tractability of our chosen biological target classes are key determinants of success and failure in our drug discovery programs.

3:20 Poster and Exhibit Viewing and Refreshment Break

3:45 Chemogenomic and Computational Annotation of Compounds and Targets
Dr. Michal Vieth, Chemoinformatics Leader, Discovery Chemistry Research, Lilly Research Laboratories
Experimental and computational methods are frequently used to annotate compounds and targets. Molecular properties and structural fragments can be used to draw observations about drugs with different route of administration. Analysis of the distribution of properties and structures of oral drugs will be presented. Selectivity data can be used to define medicinally relevant target space. Lessons from the first dendrogram of kinases based entirely on small molecule selectivity data will be described.

4:15 Subgraph Isomorphism, the RTECS database: Steps Towards a Chemist Friendly Toxicity Liability System
Dr. Ajay, Principal Scientist, Chemistry and Preclinical Algorithms, Celera
Drug design and development is fundamentally a process of finding the right compromise between multiple objective functions (activity, toxicity, absorption, etc.) I will describe a set of tools that chemists use within Celera for getting a handle on potential toxic liabilities. This system uses a fast implementation of the subgraph-isomorphism algorithm along with the RTECS database. The tool offers potential hypotheses for in vitro Tox results as well as suggests potential liabilities in compounds before synthesis and is integrated into our in-house database browser and SAR tool, Seurat.

4:45 Panel Discussion

5:15 Close of Conference

5:30-6:30 Early Registration for Validation and Results from Virtual Screening conference