Methods for Discovering and Targeting Druggable Protein-Protein Interfaces and Their Application to Repurposing

Author:

Ozdemir, E Sila

Halakou, Farideh

Nussinov, Ruth

Gursoy, Attila

Keskin, Ozlem
Author Address

Department of Chemical and Biological Engineering, Koc University, Istanbul, Turkey., Department of Computer Engineering, Koc University, Istanbul, Turkey., Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA., Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel., Department of Computer Engineering, Koc University, Istanbul, Turkey. agursoy@ku.edu.tr., Department of Chemical and Biological Engineering, Koc University, Istanbul, Turkey. okeskin@ku.edu.tr.,

Abstract:

Drug repurposing is a creative and resourceful approach to increase the number of therapies by exploiting available and approved drugs. However, identifying new protein targets for previously approved drugs is challenging. Although new strategies have been developed for drug repurposing, there is broad agreement that there is room for further improvements. In this chapter, we review protein-protein interaction (PPI) interface-targeting strategies for drug repurposing applications. We discuss certain features, such as hot spot residue and hot region prediction and their importance in drug repurposing, and illustrate common methods used in PPI networks to identify drug off-targets. We also collect available online resources for hot spot prediction, binding pocket identification, and interface clustering which are effective resources in polypharmacology. Finally, we provide case studies showing the significance of protein interfaces and hot spots in drug repurposing.

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