Structural & Computational Chemistry Agenda

Improvements in Docking Scoring Functions: The Physics-Based Perspective
Xavier Barril, Research Professor, University of Barcelona, Spain

This talk will discuss the application of first-principle simulations to improve docking performance, focussing on three different aspects: the internal energy of ligands, the kinetics of binding and the protein-ligand binding free energy.

Separating Good Models from Bad: The Role of Experimental Structural Information in Validation and Calibration
John Liebeschuetz, Head of Research, Cambridge Crystallographic Data Centre, United Kingdom

The talk explores the role of experimental small molecule structural information for the validation of structural models and the calibration of computational methods, in the fields of protein crystallography, drug design and crystal engineering.

Coffee Break & Networking in Exhibition Hall

Protein-Ligand Binding Free Energy and Kinetics
Andrea Cavalli, Associate Professor, University of Cambridge, United Kingdom

Protein-ligand binding free energy is fundamental to evaluate the affinity of a small molecule for its biological counterpart. Binding kinetics has recently emerged as a key factor influencing in vivo drug efficacy. By means of molecular dynamics simulations and enhanced sampling methods, we can try to estimate protein-ligand binding free energy and kinetics.

Rigorous Free Energy Calculations in Drug Discovery: Applications and Pitfalls
Jonathan Essex, Head, University of Southampton, United Kingdom

In this presentation, the use of rigorous free energy calculations in the drug discovery context will be described. Particular emphasis will be placed on addressing the applicability of these methods to lead identification and optimisation, and the consequences of the approximations made in affecting their accuracy.

Lunch & Networking in Exhibition Hall

Poster Viewing Session

PELE: Low Cost Protein-Ligand Dynamics and Induced Fit
Victor Tasies, Research Professor, Barcelona Supercomputing Center, Spain

PELE (Protein Energy Landscape Exploration), combining protein structure prediction techniques with Monte Carlo sampling, allows the description of ligand dynamics at a fraction of the cost of molecular dynamics.

Coffee Break & Networking in Exhibition Hall

Computational Exploration of Transient Ligand-Binding Pockets and Tunnels in Proteins
Rebecca Wade, Group Leader, Heidelberg Institute for Theoretical Studies, Germany

The dynamic nature of protein structures provides challenges and opportunities for ligand design. I will describe computational approaches to identify and characterize transient ligand-binding pockets and tunnels in proteins and discuss their application in structure-based drug design.

Virtual and Experimental Fragment Screening on GPCRs
Gyorgy Keseru, Scientific Advisor, Hungarian Academy of Sciences, Hungary

The talk addresses the identification and optimization of fragment hits on GPCR targets using both in silico and experimental approaches. Hit finding strategies and early optimization of validated and specific hits will be discussed with case studies.

In Silico Screening for Novel Escort Molecules to Overcome Multidrug Resistance Efflux
Mire Zloh, Director of Structural Chemistry Unit, University College London, United Kingdom

Overcoming efflux pumps in multidrug resistance cell is a major challenge in treatment of infection, tumours and parasites. A novel in silico approach was developed to screen for escort molecules that could restore activity of a therapeutic.

Drinks Reception

Approaches to Address Protein Flexibility in Molecular Docking
Sander Nabuurs, Head Molecular Modelling and Computational Chemistry, Lead Pharma, Netherlands

An important but complex aspect of structure-based drug design is accurately modelling receptor flexibility. This contribution will focus on different approaches we have developed to address protein flexibility in modelling protein-ligand complexes. This ranges from the prediction of binding site plasticity to the improved ranking and scoring of induced fit docking solution utilizing protein structure validation techniques.

Novel Target Family-Centric Scaffolded Libraries Applying the Privileged Structure Concept: Unlocking the Kinase, PDE, GPCR, and Epigenetic Target Space
Gerhard Mueller, Senior Vice President, Mercachem BV, Netherlands

Novel privileged structure concepts are introduced to unlock the therapeutic value of most relevant target families, such as PDEs, GPCRs, kinases and epigenetic targets.

Coffee Break & Networking in Exhibition Hall

Computational Approaches for Predicting Targets and Side Effects of Bioactive Compounds
Didier Rognan, Director of Research, University of Strasbourg, France

Predicting the molecular targets responsible for the main side effects of lead compounds is nowadays affordable thanks to the increasing availability of target-ligand binding data and the development of computational approaches to mine and predict novel target-ligand associations.

ADMET Rationalisation and Prediction in Drug Discovery: Can Computational Chemistry Reduce Compound Attrition
Alexander Alex, Director, Alex Alexander Consulting, United States of America

Compound attrition is one of the major challenges in drug research, impacting productivity and preventing potential new chemical entities reaching the market. Understanding the factors which influence attrition as early as in the compound design stage prior to synthesis is critical for preventing potential ADMET liabilities in compound development. Therefore the effective utilisation of computational approaches to rationalise and predict potential ADMET issues early is crucial in assisting compound designers in understanding, preventing and managing compound attrition risk.

Lunch & Networking in Exhibition Hall

Poster Viewing Session

Docking for GPCR Ligands -- Lessons Learned from X-Ray Structures and Homology Models
Peter Kolb, Emmy Noether Junior Group Leader, Philipps University Marburg, Germany

GPCRs have recently come into the focus of researchers using structure-based drug design methods. Examples from two applications will be presented.

Driving GPCR Structure-Based Drug Design using Stabilised Receptors: Identifying & Optimizing Hits to Leads and Computational Drugability Assessments
Jonathan Mason, Chief Scientist, Heptares Therapeutics, United Kingdom

The use of StaR™ technology to stabilize GPCRs and enable crystallography with both weak and potent ligands, biophysical screening (fragments) & mapping (BPM®) will be discussed, with examples of virtual & fragment screening hit identification and computational analyses of a broad set of X-ray structures using a GRID/WaterMap/SZMAP analyses to highlight protein ligand preferences, water energetics and thence drugability assessments.

Coffee Break & Networking in Exhibition Hall

Automating QSAR Modelling to Drive Compound Design
Stephen Pickett, Manger, GlaxoSmithKline, United Kingdom

Development of local and global QSAR models remains a key requirement for many drug discovery programs; however increasing pressure on resources means that experts in specific statistical tools are not always available. Here we present the QSAR Workbench for building and managing QSAR models and describe how it is important to ensure appropriate experimental design within the program team to maximize the benefits of local QSARs.

ANCHOR.QUERY: Rapid Discovery of Multiple Scaffold Series of p53 mdm2 Antagonists
Alexander Doemling, Chair, University of Groningen, Netherlands

Our novel designer software (ANCHOR.QUERY) together with very efficient and versatile multicomponent reaction chemistry allows for the simultaneous discovery of multiple scaffolds for the cancer target protein protein interactions p53/mdm2 and mdmx, validated by multiple biophysical methods including cocrystal structures.

Close of Conference