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High Throughput in-silico screening in HPC architectures for new inhibitors for treatment of blood diseases

Project BLOODINH
Research Area Bio Sciences
Principal Investigator(s) PD Dr. Wolfgang Wenzel
Institution(s)
  • Karlsruhe Institute of Technology, Karlsruhe, Germany

Abstract

Based on the stochastic tunneling method (STUN), a novel strategy for high-throughput in-silico screening of large ligand databases has been developed, named FlexScreen. Each ligand of the database is docked against the receptor using an all-atom representation, and the ligands with the best evaluated affinity are selected as lead candidates for drug development. Using the thymidine kinase inhibitors, the shortcomings of rigid receptor screens in a realistic system were documented. A gain in both overall binding energy and overall rank of the known substrates when two screens with a rigid and flexible (up to 15 sidechain dihedral angles) receptor are compared, is demonstrated. STUN suffers only a small loss of efficiency when an increasing number of receptor degrees of freedom is considered. FlexScreen thus offers a viable compromise between docking flexibility and computational efficiency to perform fully automated database screens on hundreds of thousands of ligands. Enrichment rates of rigid, soft and flexible receptor models for 12 diverse receptors were also investigated. A flexible sidechain model for up to 12 aminoacids increased both binding propensity and enrichment rates: EF_1 values increased by 35% on average with respect to rigid-docking. Using this flexible receptor model we are interested in the investigation of new inhibitors for the treatment of blood diseases like blood coating. Antithrombin is the main target in our study, as it regulates clotting when interacting with Thrombin. At the moment mainly heparin-based inhibitors have been designed, but they have some undesirable side effects that can complicate the disease treatment. Using our approach we intend to screen large ligand databases, obtain hits, and refine them in order to design new inhibitors against blood clotting and with no side effects, therefore we need the use of HPC resources in order to carry out all the necessary docking calculations and beyond we seek to use infrastructures services provided by DEISA in terms of UNICORE and OGSA-DAI.

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