New computational method for drug discovery

11 07 2018
The graphical image used for the cover of the JCTC (see picture below). Image: Daria Kokh/HITS

HITS researchers developed tauRAMD, a tool to predict drug-target residence times from short simulations. The method is illustrated on the cover page of July 2018 issue of the Journal of Chemical Theory and Computation, software is freely available.

The design of a drug with a desired duration of action, whether long or short, is usually a complicated and expensive trial-and-error process guided only by a mix of expert intuition and serendipity. One of the parameters affecting drug efficacy is the lifetime of the complex formed between a drug and its target protein, whose function must be altered, e.g. inhibited. In practice, many possible chemical compounds have to be synthesized and then tested to discover an appropriate drug candidate.

Easy method and high performance

As a part of the Kinetics for Drug Discovery (K4DD) project supported by the EU/EFPIA Innovative Medicines Initiative Joint Undertaking, researchers at the Molecular and Cellular Modeling (MCM) group at the Heidelberg Institute for Theoretical Studies (HITS) developed a computationally efficient and easy-to-use method for predicting the relative lifetimes of complexes of a target protein with different drug candidates. The scientists demonstrated the high predictive performance of the computational approach using experimental data measured by collaborators at Merck KGaA (Darmstadt), Sanofi-Aventis Deutschland (Frankfurt am Main), and Sanofi R&D (Vitry-sur-Seine, France).

The method, called tauRAMD (residence time, tau, estimation using Random Acceleration Molecular Dynamics simulations) has been developed for ease of use and makes it possible to compute long residence times with short simulations. It has been successfully applied to diverse sets of compounds binding a range of therapeutically important target proteins. It is described in an open-access publication (https://pubs.acs.org/doi/abs/10.1021/acs.jctc.8b00230), and the software is freely available here:  http://www.h-its.org/downloads/ramd/ 

Publication:

Estimation of Drug-Target Residence Times by τ-Random Acceleration Molecular Dynamics Simulations. Daria Kokh*, Marta Amaral, Joerg Bomke, Ulrich Grädler, Djordje Musil, Hans-Peter Buchstaller, Matthias K. Dreyer, Matthias Frech, Maryse Lowinski, Francois Vallee, Marc Bianciotto, Alexey Rak, and Rebecca C. Wade*.  J. Chem. Theory Comput., 2018, 14 (7), pp 3859–3869. DOI: 10.1021/acs.jctc.8b00230

*corresponding authors

Scientific contact:

Prof. Dr. Rebecca Wade
Molecular and Cellular Modeling Group
Heidelberg Institute for Theoretical Studies (HITS)
Phone: +49 6221 – 533 – 247
rebecca.wade@h-its.org

Media Contact:

Dr. Peter Saueressig
Head of Communications
Heidelberg Institute for Theoretical Studies (HITS)
Phone: +49 6221 533 245
peter.saueressig@h-its.org

The cover image of JCTC, July 2018, illustrates the TauRAMD method which is based on the Random Acceleration Molecular Dynamics technique and designed for computation of the relative residence times, tau, of drug-like compounds. (image by: Daria Kokh, HITS; courtesy of: JCTC)

About HITS

The Heidelberg Institute for Theoretical Studies (HITS) was established in 2010 by the physicist and SAP co-founder Klaus Tschira (1940-2015) and the Klaus Tschira Foundation as a private, non-profit research institute. HITS conducts basic research in the natural sciences, mathematics and computer science, with a focus on the processing, structuring, and analyzing of large amounts of complex data and the development of computational methods and software. The research fields range from molecular biology to astrophysics. The shareholders of HITS are the HITS-Stiftung, which is a subsidiary of the Klaus Tschira Foundation, Heidelberg University and the Karlsruhe Institute of Technology (KIT). HITS also cooperates with other universities and research institutes and with industrial partners. The base funding of HITS is provided by the HITS Stiftung with funds received from the Klaus Tschira Foundation. The primary external funding agencies are the Federal Ministry of Education and Research (BMBF), the German Research Foundation (DFG), and the European Union.

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