Friday, October 26th, 2007 in the Benzon Auditorium

Faculty of Pharmaceutical Sciences (PHARMA), University of Copenhagen, Universitetsparken 2, 2100 Copenhagen Ø

As Professor Tommy Liljefors is now retiring from the Faculty of Pharmaceutical Sciences after thirteen years of dedicated service, this minisymposium reflecting some of his interest areas has been arranged to honour his important work and contributions within the field of computational chemistry. You are cordially invited to participate.

13:00-13:10
Welcome by Thomas Balle, University of Copenhagen, PHARMA

13:10-14:00
Prof. James P. Snyder, Emory University
How Much Energy does a Small Molecule Pay to Bind to a Protein?

14:00-14:50
Prof. Gabriele Cruciani, University of Perugia
Merging Chemical and Biological Space Using a Common Reference Framework

14:50-15:20
Coffee break

15:20-16:10
Prof. Heather Carlson, University of Michigan, Ann Arbor
Pharmacophore Models for Flexible Proteins

16:10-16:35
Dr. Klaus P. Bøgesø, Vice President, Lundbeck Research DK
Tommy Liljefors and 25 Years of Computational Chemistry
Collaboration with Lundbeck

16:35-17:00
Prof. Flemming S. Jørgensen, University of Copenhagen, PHARMA
Biostructural Research at PHARMA - Today and Tomorrow

17:00 - 17:45
Drinks and snacks

Abstracts

James P. Snyder, Ana Alcaraz, Seth Childers, Yong Jiang, Scott Johnson, Andy Prussia, Pahk Thepchatri, Suwipa Saen-oon, Jennifer Sorrells

How Much Energy Does a Small Molecule Pay to Bind to a Protein?

If a molecule in equilibrium with one or more conformers in solution is characterized by a relative  DG° > 3 kcal/mol, its population is < 99.4% at 298 K. Chemists use this rule-of-thumb to rationalize yields and relative rates of reactions, while medicinal chemists apply it to the ligand-protein binding process. If the conformational strain of a drug or ligand conformation is much higher than 3 kcal/mol, it is believed by many that such a ligand has a low probability of binding to its macromolecular target. Over the past 10 years, several computational studies have attempted to verify the 3-kcal rule. With conflicting interpretations placing the accessible energy window somewhere between 3 and 40 kcal/mol, agreement has yet to be reached. The most comprehensive and recent study on 150 proteins complexed with

drug-like ligands by Perola and Charifson (J. Med. Chem. 2004, 47, 2499-2510) suggests that global strain energies of 10 kcal/mol are common (i.e. at least 10% of ligands), while 25 kcal/mol ligand strain energy can be tolerated within protein-ligand complexes. In the present study, we examine this concept by evaluating structures and energies of both bound and “free” ligands; namely X-ray structures for the former and conformationally generated global minima for the latter. By combining molecular mechanics

calculations, the fits of small molecules to X-ray crystallographic densities and NMR analysis of the conformations of ligands in solution, we conclude that it is likely that drug conformational strain energy rarely exceeds 3-5 kcal/mol in the protein binding event.

Gabriele Cruciani, Simone Sciabola, Massimo Baroni

Merging Chemical and Biological Space Using a Common Reference Framework

A fast new algorithm (FLAP) able to describe small molecules and protein structures using a common reference framework of 4-point pharmacophore fingerprints and a molecular-cavity-shape will be described. Identified particular Target locations where an energetic interaction with small molecular features would be very favorable, the Target locations are then used by FLAP to build all possible 4-point pharmacophores present in the given Target site. A related approach can be applied to small molecules, to identify pharmacophoric features, and this complementary description of Target and ligand then leads to several novel applications. FLAP can be used for selectivity studies or similarity analyses in order to compare macromolecules without superposing them. Protein families can be compared and clustered into target classes, without  bias from previous knowledge and without requiring protein superposition, alignment, or knowledge-based comparison. This paper presents the background to the new procedure, and includes case studies illustrating relevant applications of the new approach.

Heather Carlson

Pharmacophore Models for Flexible Proteins

In the multiple protein structure (MPS) method, a collection of protein conformations is used to represent the ensemble of states available to a flexible receptor. Each conformation is mapped with probe molecules and then combined to identify "consensus" regions where the requirements for complementing the receptor are consistent over many conformations. The probes in the consensus regions are translated into a pharmacophore model which describes the essential interactions but does not introduce any limits in the flexible areas. Experimental testing has shown that the technique is useful for pushing discovery into new chemical space with inhibitors of different sizes, shapes, chemical content and scaffolds. Applications to HIV-1 protease and the cancer target p53-MDM2 will be shown.  In particular, inhibitors have been identified for a new pocket in HIV-1 protease; the inhibitors are half the molecular weight of existing therapies and may eventually yield new therapeutics with better pharmacokinetic properties.

Organised/sponsored by

 
The symposium is a Drug Research Academy event organised by Thomas Balle, Department of Medicinal Chemistry, The Faculty of Pharmaceutical Sciences, University of Copenhagen, e-mail tb(at)farma.ku.dk.

The participation is free of charge and is open for attendance by all interested parties. No registration is required.