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Discovery of selective inhibitors for cyclic AMP response element-binding protein

a combined ligand and structure-based resources pipeline

Muneer, Iqraa,*; ul Qamar, Muhammad T.b,*; Tusleem, Kishverc; Abdul Rauf, Sadafd; Hussain, Hafiz M.J.a; Siddiqi, Abdul R.e

doi: 10.1097/CAD.0000000000000727
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Bromodomains are epigenetic readers of acetyl-lysine involved in chromatin remodeling and transcriptional regulations. Over the past few years, extensive research has been carried out to discover small-molecule inhibitors against bromodomains to treat various diseases. Cyclic AMP response element-binding protein (CREBBP) bromodomain has emerged as a hot target for cancer therapy. This study aims at discovering new inhibitors against CREBBP bromodomain using ligand-based molecular docking. A library of 2168 lead-like compounds were docked into the Kac binding site of CREBBP bromodomain. On the basis of the energy score and interaction analysis, six compounds were selected. In order to validate the stability of these six protein–ligand complexes 20 ns molecular dynamics simulations and principal component analyses were carried out. Based on the different analyses these six compounds may provide valuable information for developing CREBBP selective inhibitors.

aSchool of Life Sciences, University of Science and Technology of China, Hefei

bCollege of Informatics, Huazhong Agricultural University

cSchool of Medicine, Jianghan University, Wuhan, People’s Republic of China

dDepartment of Computer Science, Fatima Jinnah Women University, Rawalpindi

eDepartment of Biosciences, COMSATS University, Islamabad, Pakistan

* Iqra Muneer and Muhammad T. ul Qamar contributed equally to the writing of this article.

Correspondence to Muhammad T. ul Qamar, PhD, College of Informatics, Huazhong Agriculture University, Wuhan 430070, People’s Republic of China Tel: +86 152 7191 5965; e-mail: m.tahirulqamar@webmail.hzau.edu.cn

Received July 30, 2018

Accepted November 12, 2018

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