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WEDNESDAY, MAY 14

8:30 Chairperson’s Remarks

8:40 Utilizing Novel Technologies for Multi-Tiered CYP Inhibition Screening. 
Tatyana Zvyaga, Ph.D, Senior Research Investigator, Lead Discovery, Profiling & Compound Management, Bristol-Myers Squibb Co.
Inhibition of cytochrome P450 (CYP) enzymes by new drug candidates may cause drug interactions and adverse effects in humans. Therefore, CYP inhibition is assessed in early drug discovery settings. However, achieving both rapid and cost-effective screening for large numbers of novel compounds is challenging. This presentation will focus on leveraging novel technologies for multi-tiered CYP inhibition screening, utilizing high-throughput fully automated fluorescence-based (1536-well) and liquid chromatography-mass spectrometric (LC/MS)-based (384-well) inhibition assays, including highly integrated IT tools for automated data collection and processing. 

9:10 Mechanism-Based CYP Inhibition in Drug Discovery
Magang Shou, Ph.D., Director, Department of Pharmacokinetics and Drug Metabolism, Amgen, Inc.
Drug-drug interactions (DDIs) represent a serious concern in the discovery and development of new drugs. Mechanism-based CYP inhibition (MBI) is a common cause of the DDIs via a significant change in the exposure of one drug (victim) caused by a second drug (perpetractor). The purpose of this presentation is to introduce the concepts and experimental approaches of MBI, screening of new chemical entities (NCEs) and prediction of the human DDIs from in vitro MBI data at pharmaceutical settings. In addition, the factors that affect evaluation and prediction of MBI-mediated DDIs will also be discussed. 

9:40 Ultra-High Throughput CYP450 Inhibition to Assess Potential Drug-Drug Interactions Using the MetaChip Platform
Jonathan S. Dordick, Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute
The MetaChip technology enables early-stage, high-throughput analysis of CYP450 inhibition profiles. These chips employ human CYP450 isoforms individually or in highly controlled combinations in volumes as low as 20 nL. As a result, complete IC50 profiles of drug candidates can be achieved in minutes with micrograms of candidate compounds. The MetaChip is designed to be integrated into standard lab automation equipment. As a result, pharma can make better educated decisions on which compounds to take forward, accelerate drug development times, and reduce investment in late-stage drug failures.

10:10 Networking Coffee Break in the Exhibit Hall

10:55 Permeability and Transporter Models in Lead Role of PAMPA, Caco-2, P-gp and Beyond...
Praveen V. Balimane, Ph.D., Senior Research Investigator, Metabolism and PK, Bristol-Myers Squibb Co.
The significant issue of “attrition” faced by the pharmaceutical business can be addressed by developing and implementing appropriate models in early/late stage discovery to select the right compound with the right characteristics of “develop-ability”. Assessment of permeability/absorption and the potential to interact with efflux transporters (P-gp and others) is a key characteristic that needs to be optimized very early in discovery. The talk will discuss the newer tools such as PAMPA that can be used synergistically with established models such as Caco-2 cells to develop screening strategies in discovery. The range of profiling tools (primary high-throughput models to secondary/tertiary mechanistic models) typically used in Pharma will be discussed with their pros and cons. Transporter assays (P-gp and others) and their integration into the screening paradigm for lead optimization will also be covered. Several recent case studies will be discussed to highlight the bottom-line impact of these assays in lead optimization. 

11:25 Drug Transporters in Discovery Research and Early Drug Development - What, When and How? 
Louis Leung, Ph.D., Associate Director, Biotransformation, Drug Safety & Metabolism, Wyeth Research
The role of drug transporters in ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) has gained increasing recognition during the past decade. As a result, there is a continued need or desire to identify, at the earliest stage possible, potential drug transporter-related issues during drug discovery and development. In this presentation, the strategies in addressing potential issues relating to drug transporters will be discussed. Particular emphases are placed on what, when and how the different types of drug transporters will be evaluated during discovery research and early drug development, as well as on the assessment of their potential clinical implications.

12:55 Session Break

1:10 Chairperson’s Remarks

1:15 Structure-Based Approach to Core Hopping
Mee Shelley, Ph.D., Senior Applications Scientist, Schrodinger
Modifying the core of a lead compound to create structurally distinct chemotypes that have similar or improved binding properties is an important part of drug discovery. The majority of scaffold hopping methods in the literature use ligand-based descriptors in a search for core replacements. However, the search can be focused on a more relevant chemical space by utilizing structural information from the receptor. In this presentation, we will describe a structure-based core hopping method in CombiGlide which can systematically evaluate and rank a large collection of candidate core structures in the presence of the receptor. We will present validation of this method on known systems followed by several examples in which this method has been used to identify novel scaffolds.

1:45 Enhancing Target Design and Selection in the Early Portfolio
Robert Maguire, Ph.D., Senior Principal Scientist, Cardiovascular, Metabolic and Endocrine Diseases, Pfizer Global Research and Development, Groton/New London Labs
This talk describes how an analysis of the physical properties of Pfizer lead series and candidates can be used to influence the design, selection criteria and optimization for library sets in early programs. The approach uses readily available physical property calculations to define design zones that are subsequently populated with target molecules to ‘shape’ the library and increase the probability of identifying lead compounds with ‘drug-like’ physical properties and room for more facile optimization.

2:15 Maximizing Return on Triage Decisions in Early Lead Discovery
Simon Xi, Pfizer, Inc.
Triaging small molecule hits identified in high-throughput screens plays a pivotal role in the progression of many drug development programs. At Pfizer, triage is defined as a process that uses chemical criteria (structure and properties) and biological data to select chemical series for lead development for valued drug targets. In order to make this process more efficient and carry greater impact, we have formalized a staged approach to triage that brings to bear both drug development experience and advanced computational tools. We feel this approach will play a significant role in shortening the timeline for reaching proof-of-concept decisions earlier in lead discovery. 

2:45 Ice Cream Refreshment Break in the Exhibit Hall 
(Last Chance for Viewing)

3:30 Side Effect Profile Prediction: How to Avoid “Dirty” Chemical Features in Lead Optimization
Josef Scheiber, Ph.D. Postdoctoral Fellow, Lead Discovery Informatics/Safety Profiling, Novartis Institutes for BioMedical Research
This talk will describe a novel method to predict adverse side effects from the chemical structure only. By employing clinical databases along with chemical information, the chemical features can be identified that are most likely the reason for a certain side effect. This information can then be employed in early drug discovery. It is possible to avoid chemical moieties regarded as unsafe in the lead optimization process.

4:00 Computational Approaches to Scaffold Hopping
Ingo Muegge, Ph.D., Senior Principal Scientist, Boehringer Ingelheim Pharmaceuticals, Inc.
Virtual screening and de novo design are two computational techniques that have been applied successfully in the past to generate new hits and lead candidates in early drug discovery. Here we focus on how these well known computational approaches can guide us toward new scaffolds with different and hopefully more favorable properties starting from known ligands – a process sometimes referred to as scaffold hopping.

4:30 Lead Hopping via QSAR and a 10 Million e-Compound Collection
S. Stanley Young, Ph.D., Assistant Director of Bioinformatics, National Institute of Statistical Sciences
Often you will have access to a training data set and would like to find additional active molecules. ChemModLab, a free web service, gives sophisticated QSAR analysis with 80 different models. The models from ChemModLab can be used as an ensemble and used to virtually screen over 10M commercially available compounds. The resulting list can be diversity selected and used for a lead-hopping campaign. 

5:00pm Close of Conference