Identifying Novel Drug Targets by iDTPnd: A Case Study of Kinase Inhibitors
- Author:
Naveed HAMMAD
1
,
2
;
Reglin CORINNA
;
Schubert THOMAS
;
Gao XIN
;
T.Arold STEFAN
;
L.Maitland MICHAEL
Author Information
1. Toyota Technological Institute at Chicago,Chicago,IL 60637,USA
2. Department of Computer Science,National University of Computer and Emerging Sciences,Islamabad 44000,Pakistan
- Keywords:
Protein–drug interaction;
iDTPnd;
Kinase inhibitor;
Drug-binding site signature;
Drug repurposing
- From:
Genomics, Proteomics & Bioinformatics
2021;19(6):986-997
- CountryChina
- Language:Chinese
-
Abstract:
Current FDA-approved kinase inhibitors cause diverse adverse effects, some of which are due to the me-chanism-independent effects of these drugs. Identifying these mechanism-independent interactions could improve drug safety and support drug repurposing. Here, we develop iDTPnd (integrated Drug Target Predictor with negative dataset), a computational approach for large-scale discovery of novel targets for known drugs. For a given drug, we construct a positive structural signature as well as a negative structural signature that captures the weakly conserved structural features of drug-binding sites. To facilitate assessment of unintended targets, iDTPnd also provides a docking-based interaction score and its statistical significance. We confirm the interactions of sorafenib, imatinib, dasatinib, sunitinib, and pazopanib with their known targets at a sensitivity of 52％and a specificity of 55％. We also validate 10 predicted novel targets by using in vitro experiments. Our results suggest that proteins other than kinases, such as nuclear receptors, cytochrome P450, and MHC class I molecules, can also be physiologically relevant targets of kinase inhibitors. Our method is general and broadly applicable for the identification of protein–small molecule interactions, when sufficient drug–target 3D data are available. The code for constructing the structural signatures is available at https://sfb.kaust.edu.sa/Documents/iDTP.zip.
