Property-Based Drug Design in Medicinal Chemistry Track Heaer

As the need for newer and more effective drugs evolves, so do the tools and techniques for drug discovery. Property-based drug design allows researchers and chemists to design drug candidates with the right balance of physiochemical (ADME profiles) and biophysical properties. The fifth annual Property-Based Drug Design in Medicinal Chemistry conference will focus on experimental and in silico approaches to best determine, exploit, and optimize physical properties in order to enhance efficacy, optimize ADME, and reduce toxicity. Conventional small molecules, macrocycles, and protein-protein targets will be addressed. The conference will bring together academic and industry experts to discuss advances in new and evolving technologies and methods, such as data-driven and computational design, molecular metrics, data management, and analysis.

Program Advisors: 

Terry Richard Stouch, Ph.D., President, Science for Solutions, LLC 

John Reilly, Ph.D., Senior Research Investigator, Global Discovery Chemistry, Novartis Institute of Biomedical Research 

Peter Kenny, Ph.D., Visiting Scientist, NEQUIMED-IQSC, University of Sao

Final Agenda

Thursday, June 16

11:00 am Registration.

12:00 pm Bridging Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:30 Session Break

1:00 Coffee and Dessert in the Exhibit Hall with Poster Viewing


3:30 Refreshment Break in the Exhibit Hall with Poster Viewing


4:15 Chairperson’s Opening Remarks

Terry Richard Stouch, Ph.D., President, Science for Solutions, LLC


Nick_MeanwellNicholas A. Meanwell, Ph.D., Executive Director, Discovery Chemistry, Bristol-Myers Squibb

Contemporary drug design practices have been criticized for a tendency to produce candidates with higher molecular weight that are more lipophilic and rely more heavily on sp2 centers than traditional drug space. In this presentation, background discussion on the observations will be summarized along with a synopsis of some of the strategies that are being adopted to address these concerns that include the application of guidepost efficiency indices and the design of candidates with improved physical properties.

5:10 Design Considerations for Macrocycles

Adrian_WhittyAdrian Whitty, Ph.D., Associate Professor, Chemistry, Boston University

Progress in developing synthetic macrocycles as leads and drugs has been slow, in part due to uncertainty concerning what kinds of macrocyclic structures will possess good prospects for strong target binding and favorable ADME properties. I will discuss recent advances in understanding what structural and physicochemical properties of macrocycles might confer good utility for drug discovery, and what properties make a protein target appropriate for inhibition by macrocyclic compounds.

5:40 Computational and Physical Properties of Orally Bioavailable Cyclic Peptides

Alan_MathiowetzAlan Mathiowetz, Director, Worldwide Medicinal Chemistry, Cardiovascular and Metabolic Diseases, Pfizer

An increasing number of orally bioavailable cyclic peptides have been discovered in recent years, providing us with an opportunity to identify the design principles for achieving improved permeability in this traditionally challenging physical property space. A variety of computational parameters and measured physical properties will be discussed, describing their relationship to permeability and other ADME properties – both across a broad dataset of compounds and for specific published orally bioavailable peptides.

6:10 FEATURED POSTER PRESENTATION: EPSA: A Novel Supercritical Fluid Chromatography Technique Enabling the Design of Permeable Cyclic Peptides

Gilles_GoetzGilles Goetz, Ph. D., Principal Scientist, Analytical Chemistry, Pfizer

Applications of a new chromatographic method using SFC technology developed recently at Pfizer are described here. The EPSA method, as a readout of polarity, correlates retention on a specific stationary phase with the exposed polarity of a molecule. Changes in retention can be interpreted by changes in polarity induced by the presence of Intra-molecular Hydrogen Bonding (IMHB): indeed, IMHBs tend to impact molecular conformation, inducing hidden polarity that results in a decrease in analyte retention on the EPSA support. We demonstrate here the impact of this method on multiple Beyond Rule of 5 projects (NS5A, Oxytocin Receptor, others). Given that conformational changes (induced and/or stabilized by the formation of IMHB) increases potential for membrane permeability, we show here that EPSA, and the EPSA prediction model, have significant impact in drug design.

6:25 Close of Day

6:30 Dinner Short Course Registration.

7:00 - 9:30 Dinner Short Courses

Friday, June 17

7:15 am Registration.

7:30 Interactive Breakout Discussion Groups with Continental Breakfast

This session features various discussion groups that are led by a moderator/s who ensures focused conversations around the key issues listed. Attendees choose to join a specific group and the small, informal setting facilitates sharing of ideas and active networking. Continental breakfast is available for all participants. 

Topic: Routine use of QSAR Models in Medicinal Chemistry  

Moderator: Dan Ortwine, Principal Scientist, Discovery Chemistry, Genentech

  • How does one get property-calculating QSAR models used routinely by Medicinal Chemists?
  • How are models deployed and updated across the organization?
  • What is the best strategy for training users in their use?
  • How often should models be updated?

Topic: Physical Properties of Orally Bioavailable Cyclic Peptides  

Moderator: John Reilly, Ph.D., Senior Research Investigator, Global Discovery Chemistry, Novartis Institute of Biomedical Research

  • What physicochemical strategies have you used to optimize designing peptides to cross the gut wall via a passive transcellular mode – logD, pKa, clogP, EPSA methods
  • Do you see computational models being more benefit in this area?
  • Do you think the benefits outweigh the concerns of working within orally bioavailable cyclic peptide space – what are your experiences?

Topic: Designing Molecules Beyond the Rule of 5  

Moderator: David DeGoey, Ph. D., Sr. Principal Research Scientist, Discovery Chemistry and Technology, AbbVie

  • What strategies are good for optimizing permeability, solubility and clearance bRo5?
  • What are the most important properties to optimize for achieving good oral bioavailability bRo5?
  • What’s the role of and how important is active transport in the absorption of compounds bRo5?



8:35 Chairperson’s Remarks

Ed Champness, CSO, Optibrium

8:45 CNS Drug Design: A Delicate Balancing Act

Zoran_RankovicZoran Rankovic, Ph.D., Research Fellow, Discovery Chemistry Research & Technologies, Eli Lilly

Designing molecules that can penetrate the Blood Brain Barrier and achieve optimal concentration at the desired therapeutic target in the brain is a specific and major challenge for medicinal chemists working in CNS drug discovery. This presentation will outline modern CNS pharmacokinetic concepts and critical physicochemical attributes of CNS drugs and drug candidates, and discuss examples of successful medicinal chemistry strategies towards brain penetrant molecules.

9:15 High-Throughput Melanin Binding Affinity and in silico Methods to Aid in The Prediction of Drug Exposure in Ocular Tissue

John_ReillyJohn Reilly, Ph.D., Senior Research Investigator, Global Discovery Chemistry, Novartis Institute of Biomedical Research

In this work, a high throughput melanin chromatographic affinity assay has been developed and validated which has allowed the rapid melanin affinity assessment for a large number of compounds. Melanin affinity of compounds can be quickly assigned as low, medium, or high melanin binders and this has been useful in predicting ocular tissue distribution within in vivo studies. This has also allowed a QSAR method to be developed which has identified several physiochemical descriptors to be considered in the design of compounds where melanin binding modulation is desired.

9:45 The Challenges of Making Decisions Using Uncertain Property Data

Ed_ChampnessEd Champness, CSO, Optibrium

This presentation considers approaches to rigorously account for uncertainties when selecting or assessing compounds against a property criterion; first for an individual measurement of a single property and then replicate measurements. We then explore how uncertainties in multiple properties can be combined when assessing compounds against a profile of criteria, a process known as multi-parameter optimisation. This guides rigorous decision-making using complex, uncertain data to focus on compounds with the best chance of success, while avoiding missed opportunities.

10:15 Coffee Break in the Exhibit Hall. Last Chance for Poster Viewing.

11:00 Discovery of a Second Generation, Pan Genotype NS3/4A Protease Inhibitor (BMS-986144) for the Treatment of HCV

Paul_ScolaPaul Scola, Ph.D., Research Fellow, Department of Virology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute

This presentation will highlight key findings that lead to the discovery of BMS-986144, a pan genotype NS3/4a protease inhibitor for the treatment of HCV. Chemotype optimization with respect to potency, PK and off-target liabilities will be discussed.

11:30 Uses of Physicochemical Properties to Predict and Optimize in vivo Drug Absorption in Preclinical and Clinical Studies

Peter Wuelfing, Ph.D., Executive Director, Discovery Pharmaceutical Sciences, Merck & Co

It is well understood now that small molecule physicochemical properties have a profound impact on developability. Prediction of development outcomes from measurements starting at high throughput solubility progressing through detailed biorelevant dissolution, permeability, and drug absorption modeling studies exist. The talk will be aimed at giving examples of detection of favorable and unfavorable properties in drug discovery and what role crystalline phase and formulation can play in enabling success.

12:00 pm Trajectories of Drug Discovery Programs: What Are the Principles Behind Success?

Rob_YoungRobert J. Young, Ph.D., Group Leader, NCE Medicinal Chemistry, GlaxoSmithKline

An analysis of decision making principles and how these influence the progress of drug discovery projects will be presented. These trajectories will demonstrate the value of efficiency metrics and physical properties as indicators of quality and how these relate to the likelihood of success. Examples will be given of the consequences of sub-optimal properties, including increased off target activity/toxicity.

12:30 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:00 Session Break


1:30 Chairperson’s Remarks

Kap-Sun Yeung, Ph. D., Principal Scientist, Discovery Chemistry, Bristol-Myers Squibb

1:35 Improving Odds of Success: Data Mining and Predictive Models to Improve Decision Making

Terry_StouchTerry Richard Stouch, Ph.D., President, Science for Solutions, LLC

Drug discovery is driven by thousands of decisions that are founded in thousands of pieces of data. Although that data is crucial, often its veracity is unknown due to many factors. Although some of these factors can be anticipated, often they are ignored and often they are unanticipated. Data validation is inhibited by cost, time, and limited material. We will discuss the tandem use of the “bigger” data of drug discovery and predictive models that can help identify problem measurements and hence improve the outcome of data-based decisions.

2:05 Beyond the Rule of 5: Lessons Learned from AbbVie’s Drugs and Compound Collection

David_DeGoeyDavid DeGoey, Ph.D., Senior Principal Research Scientist, Discovery Chemistry and Technology, AbbVie

While Lipinski’s rule of 5 describes the property space with the highest probability of achieving good oral absorption, there’s increasing focus on the pursuit of less druggable targets requiring beyond rule of 5 (bRo5) compounds that offer potential for development of promising new therapeutic agents. We present highlights of lessons learned from discovery of bRo5 compounds for the treatment of HCV and from our analysis of AbbVie’s bRo5 compound collection.

2:35 Predicting the Impact of Biopharmaceutical Properties on Pharmacokinetics

Jan_WalstromJan Wahlstrom, Ph.D., Director, Pharmacokinetics and Drug Metabolism, Amgen

Physicochemical properties and early ADME assays guide chemotype evaluation and rational scaffold alteration. This presentation will focus on the integration of these approaches with physiologically based pharmacokinetic modeling (PBPK) to enable the prediction of clinical outcomes and to optimize selection of development candidates.

3:05 Refreshment Break

3:20 Predicting Drug Induced Liver Injury Using Compound’s in vitro and in vivo Properties

Falgun_ShahFalgun Shah, Ph.D., Principal Scientist, Computational Toxicologist, Molecular Informatics, Pfizer

Severe drug-induced liver injury (DILI) remains a major safety concern for new small molecule drug candidates due to the frequency with which it occurs, idiosyncratic nature, poor prognosis, and diverse underlying mechanisms. Numerous experimental approaches have been published to improve human DILI prediction but with only modest success. The present talk will discuss the utility of human plasma exposure and/or in vitro mechanistic assays of hepatotoxic liabilities to predict DILI, using 125 drugs (70 = most-DILI, 55 = no-DILI) from the FDA’s Liver Toxicity Knowledge Base as a training set. Additionally, how these approaches can be utilized prospectively in selecting candidates with less likelihoods of DILI in clinic will be discussed.


3:50 Integrating Property- and Structure-Based Calculations: A Holistic Approach to Drug Design

Daniel_OrtwineDan Ortwine, Principal Scientist, Discovery Chemistry, Genentech

Effective drug design requires easy to use integrated desktop software that combines structure-based drug design capability with real-time delivery of calculated physiochemical and DMPK endpoints. We have deployed such software to the desktops of discovery scientists while continuing to develop scientific and data management capabilities. Routine use of such integrated software to triage molecules ahead of synthesis has accelerated the drug discovery process. Examples will be described, and best practices discussed.

4:20 Expanding the Pharmacophore of Homeostatic Enzymes Using Property and Structure-Based Approaches

Robert_FotiRobert Foti, Senior Scientist, Pharmacokinetics and Drug Metabolism, Amgen, Inc.

While the roles of CYP2D6 or CYP3A4 in xenobiotic metabolism have been well characterized, the same cannot be said for cytochrome P450 enzymes whose primary role is the homeostatic regulation of endogenous compounds such as fatty acids, steroids or retinoids. The primary aim of this lecture will be to highlight the application of property- and structural-based approaches to expand the known xenobiotic pharmacophores for homeostatic cytochrome P450 enzymes.

4:50 Close of Conference

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