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Institute for Advanced Simulation (IAS)

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Seminar by Dr. Ute Röhrig

Swiss Institute of Bioinformatics, Zurich (Switzerland)

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24 Aug 2017 11:00
end
23 Jun 2017 12:00
venue
Lecture room 2009, Jülich GRS building (16.15)

Rational Drug Design for Immuno-Oncology using Computational Tools

Immuno-oncology has delivered exciting results over the last decade, characterized by substantial and long-term clinical benefit for cancer patients. Two promising strategies to further improve clinical outcomes consist in inhibition of the hemoprotein indoleamine 2,3-dioxygenase 1 (IDO1), which plays a major role in tumor-induced immunosuppression, and in activation of the STING-controlled innate immune pathway. We are rationally designing small molecule modulators of these targets using different computational and experimental techniques. To address the challenge of treating ligand-metal interactions in docking, we developed a semiempirical quantum mechanical/molecular mechanical (QM/MM) on-the-fly docking algorithm. Benchmarking studies show that the QM/MM code preserves the accuracy of classical scores for conventional ligand-protein complexes, while it yields significant improvements for metalloproteins at moderate computational cost. Our fragment-based computational drug-design effort led to the discovery of highly efficient IDO1 inhibitors, the most active being of nanomolar potency both in enzymatic and cellular assays, while showing no cellular toxicity and a high selectivity for IDO1 over related enzymes.


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