Discovering Putative Protein Targets of Small Molecules: A Study of the p53 Activator Nutlin

Discovering Putative Protein Targets of Small Molecules: A Study of the p53 Activator Nutlin
Discovering Putative Protein Targets of Small Molecules: A Study of the p53 Activator Nutlin
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Journal of Chemical Information and Modeling
Publication Date:
22 February 2019
J. Chem. Inf. Model. 2019, 59, 1529−1546
Small molecule drugs bind to a pocket in disease causing target proteins based on complementarity in shape and physicochemical properties. There is a likelihood that other proteins could have binding sites that are structurally similar to the target protein. Binding to these other proteins could alter their activities leading to off target effects of the drug. One such small molecule drug Nutlin binds the protein MDM2, which is upregulated in several types of cancer and is a negative regulator of the tumor suppressor protein p53. To investigate the off target effects of Nutlin, we present here a shape-based data mining effort. We extracted the binding pocket of Nutlin from the crystal structure of Nutlin bound MDM2. We next mined the protein structural database (PDB) for putative binding pockets in other human protein structures that were similar in shape to the Nutlin pocket in MDM2 using our topology-independent structural superimposition tool CLICK. We detected 49 proteins which have binding pockets that were structurally similar to the Nutlin binding site of MDM2. All of the potential complexes were evaluated using molecular mechanics and AutoDock Vina docking scores. Further, molecular dynamics simulations were carried out on four of the predicted Nutlin-protein complexes. The binding of Nutlin to one of these proteins, gamma glutamyl hydrolase, was also experimentally validated by a thermal shift assay. These findings provide a platform for identifying potential off-target effects of existing/new drugs and also opens the possibilities for repurposing drugs/ligands
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Funding Info:
Funding was provided by Biomedical Research Council (A*STAR), Singapore. M.S.M. would also like to acknowledge Wellcome Trust-DBT India alliance for a senior fellowship. N.S. would like to acknowledge a CSIR-SPMF fellowship for funding. M.N.N. would like to acknowledge the Biomedical Research Council (BMRC)-Economic Development Board (EDB) Industry Alignment Fund (IAF311017G and H18/01/a0/B14), A*STAR, Singapore for funding.
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Chemical Information and Modeling, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see
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