Workpackage 1: Drug-target binding kinetics: Capturing & sharing the essence of it

Understanding the interaction of small drug molecules with their protein targets represents an important predictor for the clinical success of a drug (see "Why spend €21 million on studying kinetics?"). Such knowledge can be an important asset in developing effective treatments.

Usually very little is known about the association and dissociation rates or the residence time of a drug molecule with its target. There is also a lack of structural information, models and tools to predict the behavior of new drugs

The aim of the K4DD consortium is to better understand the mechanisms that influence the binding kinetics of drug molecules with their targets. Within K4DD, WP1 focuses on the generation of kinetic and thermodynamic data, protein-drug crystal structure analysis using x-ray and on the development of computer modeling (or in silico) tools (Figure 1).

Figure 1. Summary of the role of WP1 in the K4DD consortium

Within the human body, protein targets are located either on the surface of cells (membrane proteins) or they freely float within body fluids (soluble protein). A wide range of clinically-relevant soluble and membrane proteins is being investigated, ranging from G protein-coupled receptors (GPCRs, which are the), target of 30% of current drugs [D.Guo, 2014], to kinases and proteases. Several techniques are used in order to identify and understand all the different types of drug-target interactions. This approach of using a comprehensive set of targets, a variety of techniques [A. Zhukov, 2011],[C. Kötting, 2012], and taking a multidisciplinary approach enables us to study, analyze and conceptualize the kinetics of the drug-target interaction.

All the data generated with the consortium will be part of a unique, complete and eventually publicly accessible database.

The techniques used to obtain drug-target interaction data are typically obtained in vitro (for instance by running biochemical ligand binding assays) and in silico (simulating ligand binding by a computer program) techniques. Many of the techniques are being adapted and optimized by WP2 to allow high-throughput drug-target kinetic analysis. As the ultimate goal is to improve drug effects in human, the translation of such in vitro and in silico data to the human situation is a prerequisite. WP3 is focusing on better understanding how an in vitro drug-target kinetic change translates to the in vivo pharmacological effects of a potential drug

WP1 at a glance:

  • 7 universities
  • 7 large pharmaceutical companies
  • 3 small-and medium sized enterprises

Expertise:

  • structural biology, biochemistry, biophysics, computational science and drug discovery

Challenges:

  • biophysical techniques on membrane proteins, protein-ligand structures, complete database of kinetic and thermodynamic data

Main techniques:

  • Surface Plasmon Resonance (SPR)
  • Isothermal Titration Calorimetry (ITC)
  • Radioligand binding assay
  • Attenuated Total Reflection Fourier Transform Infrared Spectroscopy (ATR-FTIR)
  • X-ray crystallography
  • Mathematical modeling

Workpackage leaders:

  • M. Frech PhD (Matthias
  • Prof. S. Knapp PhD (Stefan)

 

 

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