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Structure-Based Drug Design - Day 3

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Friday, June 25, 2010

8:15 am Registration and Morning Coffee


New Advances in Docking

8:45 Chairperson’s Remarks

Gergely TothGergely Toth, Ph.D., University of Cambridge, UK





9:00 Docking and Scoring: From Fragments to Drug-Sized Molecules

Paul MortensonPaul Mortenson, Ph.D., Senior Research Associate, Computational Chemistry and Informatics, Astex Therapeutics Ltd.

We apply force-field based rescoring methods to a number of docking and virtual screening data sets, including a fragment set drawn from Astex’ large proprietary database of fragment structures, along with well-known publicly available benchmark sets. The results are compared with those obtained via conventional docking methods, with force-field based methods showing significantly better performance in some cases, particularly for the fragment set. Possible reasons for the variation in performance are discussed.

9:30 Dock - Score - Analyze: Novel Approaches to Structure-Based Virtual Screening

Matthias RareyMatthias Rarey, Ph.D., Professor & Managing Director, ZBH Center for Bioinformatics, University of Hamburg

Virtual screening is usually implemented as a cascade of filters with increasing complexity ending in a multitude of individual docking and scoring calculations. Performing it is still a challenge starting with protein preparation usually ending with a complex, manual analysis of the results. In this talk novel approaches and sample applications will be presented focusing on the fast structure-based prefiltering of compounds, scoring, and visualization.


Sponsored by
10:00 Fast Docking-Based Free Energy Calculation Applied to Understanding Ligand Efficiency

Jeff WisemanMatthew Clark, Ph.D., Chief Technology Officer, Pharmatrope, Ltd.

We have implemented a calculation of ligand-protein binding free energy that samples both ligand conformations and protein side-chain motions as well as interaction with explicit water in the protein binding site. The method is fast, requiring 3 cpu-hr or less for a full-sized ligand with 5-7 rotatable bonds, and requires very little set-up time, needing only a protein data file and a ligand structure file as input. Because of the speed and ease of use, we have been able to apply the calculation to multiple test systems that span 12 kcal/mol in ligand binding affinity, which in turn allows us to begin making meaningful generalizations about ligand design. We discuss the results in the context of the classic plot of binding affinity vs. ligand size (Kuntz et al, 1999) that shows the dependence of binding affinity on ligand size, or more specifically the lack thereof. 

10:15 Networking Coffee Break, Poster and Exhibit Viewing

11:00 Implementation of Protein Flexibility and Water Molecules in Docking and Scoring Methods

Nicolas MoitessierNicolas Moitessier, Ph.D., Professor, Chemistry, McGill University

Over the years, several docking program developers have implemented protein flexibility in their programs, although it has never been clearly shown to significantly improve the results. We have investigated the impact of these two factors in pose prediction, scoring functions, and identification of actives by docking-based virtual screening. This presentation will help attendees better understand the pros and cons of these implementations.


Special Case Study

11:30 Combating Drug Resistance:  Lessons from HIV Protease and Beyond

Celia SchifferCelia Schiffer, Ph.D., Professor, Biochemistry & Molecular Pharmacology, UMass Medical School






12:00 pm Poster Award presented by Elizabeth Sourial, Director, Scientific Services, Chemical Computing Group 

12:05 Lunch on Your Own

Impact of SBDD on Small Molecule
Drug Discovery

1:25 Chairperson’s Remarks

José Duca, Ph.D., Senior Principal Scientist, 3D - Drug Design Department, Merck Research Laboratories 

1:30 Beyond Growing and Linking: Impact of Fragments on the Discovery of Kinas e Inhibitors

Andreas KuglstatterAndreas Kuglstatter, Ph.D., Research Scientist, Discovery Technologies, Roche

Crystal structures of a protein drug target in complex with small molecule fragments facilitate and accelerate drug discovery in many ways beyond the conventional concepts of fragment growing and linking. At Roche, fragments bound to the protein kinases BTK, IRAK4, SYK, JNK3 and p38 were used to: 1) identify unique protein conformations that allow rational selectivity design, 2) create libraries of proprietary kinase inhibitors which serve as high quality “off-the-shelf” hits, and 3) rapidly discover novel drug candidates by hit expansion and scaffold hopping.

2:00 The Impact of Recent X-Ray Structure Determinations on Structure-Based Drug Design for GPCRs and other CNS Targets

Sid TopiolSid Topiol, Ph.D., Head of US Computational Chemistry and Structural Investigations, Chemistry, Lundbeck Research, USA

While Structure-based Design has become a powerful tool in drug discovery, its role in compound design and screening for CNS targets, which are often membrane-bound proteins, has been more limited. This has been due to the difficulty in obtaining X-ray structures for these targets. Significant recent successes in X-ray structure determinations are rapidly advancing this field. These findings, as well as early evidence of their impact on membrane protein targets such as (Class A and C) GPCRs and Transporters, are reviewed.

2:30 From Enzymes to GPCRs: Experiences with Structure-Based Design Including Fragment Screening, Biophysical Mapping and In Silico Approaches

Jonothan MasonJonathan Mason, Ph.D., Head of Computational Chemistry / Chief Scientist, Medicinal Chemistry, Heptares Therapeutic Ltd / Lundbeck Resesrch DK

The stabilized receptors (StaRs) technology used at Heptares enables SBDD approaches previously limited to soluble targets to be used, such as X-ray structures with weak ligands, biophysical mapping and fragment screening and functional binding studies. Recent results such as those from fragment screening (e.g TINS/Zobio) will be discussed and contrasted with results from several enzyme targets.

3:00 Coupling the GPCR Structural Determination Process with Discovery and Optimization of Small Molecule Ligands

Michael HansonMichael Hanson, Ph.D., Associate Director, Structural Biology, Receptos, Inc.

The successful crystal structure determination of G-protein coupled receptors is dependent on simultaneous optimization of numerous parameters including identification and iterative optimization of small molecule ligands capable of stabilizing a receptor in a unique conformation. Therefore the process of crystallization is not only a pre-requisite for structure determination and SBDD but also provides an additional tool for compound discovery and optimization through biophysical characterization of stability induction at the protein level. This stability induction can be quantified and coupled to the SAR process, utilized for mapping of binding sites through mutagenesis and aid in the process of model validation.

3:30 Closing Remarks

3:45 pm Close of Conference

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