Advances and Progress in Drug Design VIII

Sidney Topiol, Associate Director, Computational Chemistry, Lundbeck.

• Accuracy of docking for fragments
• Improving fragment docking and scoring
• Construction and application of fragment libraries
• Examples of successful fragment discovery

Chris Murray, Director, Computational Chemistry & Informatics, Astex Therapeutics.

• Scaffold hopping using 2D fingerprints
• Shape-based methods for understanding SAR
• Structure-guided optimisation of fragments and hits
• Shape-based methods for understanding SAR
• Structure-guided optimisation of fragments and hits

Richard Law, Project Leader, Computational Chemistry, Evotec.

• What is needed to do ligand-based in silico de novo drug design?
• Analyzing HTS data – separating the chaff form the wheat
• Activity cliffs – what do they tell us?
• Generating good local activity/property models
• Generating and rapidly screening new molecular entities
• Case studies
  

Walter Woltosz, Chairman and Chief Executive Officer, Simulations Plus.

• QSAR models become less predictive over time as new chemical space is explored
• Literature on times-series behaviour of QSAR models is still sparse
• Strategies to improve model predictivity will be discussed
• Need for automation is addressed
• AutoQSAR opens new era of predictive modelling to support compound quality

Rupert Austin, Associate Principal Scientist, AstraZeneca.

In this work we demonstrate that MCSS (Multiple Copy Simultaneous Search) is a powerful CHARMm-based method for docking and minimizing small ligand fragments in an active protein-binding site. The performance and ability to recover the positions of native ligand-protein complexes was investigated using a novel, fully automated, and workflow-based MCSS implementation. Accurate scoring and placement of fragment is crucial when using MCSS in fragment-based ligand design and we present validation using several small protein-fragment complexes. The results show that MCSS is able to recover the X-ray poses, and, with only some exceptions, score the pose correctly.

Jürgen Koska, Lead Scientist, Accelrys.

• Comparing ligands (virtual screening) using Molecular Interaction Fields
• Characteristion of ligands using biological fingerprints - binding, functional & chemogenomic aspects
• Some intriguing structure-based design examples - steep SAR & challenges to fragment-based approaches

Jon Mason, Divisional Director, Lundbeck Research.

• Prediction of three-dimensional structures of G-protein coupled receptors
• The significance of GPCRs
• Structure based approaches for GPCR targets
• Studies illustrating lead finding, optimization and novel template identification

Frank Blaney, Research Manager, GlaxoSmithkline.

• The design of mimics of the endogenous ligands/mediators
• The identification and use of privileged structures
• Analog research from known ligands and drugs
• Chemistry strategy utilizing knowledge-based lead generation and optimization, bioisostere evolutions, chiral switch, and ligand-based drug design

Matthias Frech, Head of Molecular Interaction & Biophysics, Merck.