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

Journal of Chemical Information and Modeling
Minh N NguyenM S Madhusudhan

Abstract

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...Continue Reading

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Citations

Jan 18, 2020·Briefings in Bioinformatics·Ammu Prasanna KumarSuryani Lukman
Dec 13, 2019·PLoS Neglected Tropical Diseases·Neeladri SenM S Madhusudhan

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