Molecular dynamics simulation reveals the possible druggable hot-spots of USP7
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Mitul Srivastava1,*, Charu Suri1,*, Mrityunjay Singh1, Rajani Mathur2 and Shailendra Asthana1
1Drug Discovery Research Center (DDRC), Translational Health Science and Technology Institute (THSTI), Faridabad, Haryana, India
2Delhi Institute of Pharmaceutical Sciences and Research, Puspvihar, New Delhi, Delhi, India
*These authors contributed equally to this work
Shailendra Asthana, email: [email protected]
Keywords: deubiquitinases enzyme; ubiquitin; docking; molecular dynamics simulation; free energy calculations
Received: May 29, 2018 Accepted: September 03, 2018 Published: September 28, 2018
The plasticity in Ubiquitin Specific Proteases (USP7) inducing conformational changes at important areas has highlighted an intricate mechanism, by which USP7 is regulated. Given the importance of USP7 in oncogenic pathways and immune-oncology, identification of USP7 inhibitors has attracted considerable interest. Despite substantial efforts, the discovery of deubiquitinases (DUBs) inhibitors, knowledge of their binding site and understanding the possible mechanism of action has proven particularly challenging. We disclose the most likely binding site of P5091 (a potent USP7 inhibitor), which reveal a cryptic allosteric site through extensive computational studies in an inhibitor dependent and independent manner. Overall, these findings demonstrate the tractability and druggability of USP7. Through a series of molecular dynamics simulations and detailed quantitative analysis, a dynamically stable allosteric binding site near catalytic center of the inactive state of USP7 (site partially absent in active state), along with two newly identified sites have been revealed, which opens the avenue for rational structure-guided inhibitor designing in USP7 specific-manner.
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