Computational insights into the binding mode of curcumin analogues against EP300 HAT domain as potent acetyltransferase inhibitors

Shivananda Kandagalla; Sharath Belenahalli Shekarappa; Hrvoje Rimac; Maria A Grishina; Vladimir A Potemkin; Manjunatha Hanumanthappa

doi:10.1016/j.jmgm.2020.107756

Computational insights into the binding mode of curcumin analogues against EP300 HAT domain as potent acetyltransferase inhibitors

J Mol Graph Model. 2020 Dec:101:107756. doi: 10.1016/j.jmgm.2020.107756. Epub 2020 Sep 16.

Authors

Shivananda Kandagalla¹, Sharath Belenahalli Shekarappa², Hrvoje Rimac³, Maria A Grishina¹, Vladimir A Potemkin⁴, Manjunatha Hanumanthappa⁵

Affiliations

¹ Laboratory of Computational Modeling of Drugs, Higher Medical and Biological School, South Ural State University, Chelyabinsk, 454080, Chaikovskogo 20A, Russia.
² Department of PG Studies and Research in Biotechnology and Bioinformatics, Kuvempu University, Jnana Sahyadri, Shankaraghatta, Shivamogga, 577451, Karnataka, India.
³ Laboratory of Computational Modeling of Drugs, Higher Medical and Biological School, South Ural State University, Chelyabinsk, 454080, Chaikovskogo 20A, Russia; Department of Medicinal Chemistry, University of Zagreb Faculty of Pharmacy and Biochemistry, Ante Kovacica 1, 10000, Zagreb, Croatia. Electronic address: hrvoje.rimac@pharma.unizg.hr.
⁴ Laboratory of Computational Modeling of Drugs, Higher Medical and Biological School, South Ural State University, Chelyabinsk, 454080, Chaikovskogo 20A, Russia. Electronic address: potemkinva@susu.ru.
⁵ Department of PG Studies and Research in Biotechnology and Bioinformatics, Kuvempu University, Jnana Sahyadri, Shankaraghatta, Shivamogga, 577451, Karnataka, India; Department of Biochemistry, Jnana Bharathi Campus, Bangalore University, Bangalore, Karnataka, 560056, India. Electronic address: manjunathh@kuvempu.ac.in.

PMID: 32979659
DOI: 10.1016/j.jmgm.2020.107756

Abstract

Acetylation plays a key role in maintaining and balancing cellular regulation and homeostasis. Acetyltransferases are an important class of enzymes which mediate this acetylation process. EP300 is a type 3 major lysine (K) acetyl transferase, and its aberrant activity is implicated in many human diseases. Hence, targeting EP300 mediated acetylation is a necessary step to control the associated diseases. Currently, a few EP300 inhibitors are known, among which curcumin is the most widely investigated molecule. However, due to its instability, chemical aggregation and reactivity, its inhibitory activity against the EP300 acetyltransferase domain is disputable. To address this curcumin problem, different curcumin analogues have been synthesized. These molecules were selected for screening against the EP300 acetyltransferase domain using in silico docking and MD analysis. We have successfully elucidated that the curcumin analogue CNB001 is a potential EP300 inhibitor with good drug-like characteristics.

Keywords: CNB001; Curcumin analogues; Docking; EP300; HAT domain; Molecular dynamics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Acetyltransferases
Curcumin* / pharmacology
E1A-Associated p300 Protein
Humans
Lysine
Protein Processing, Post-Translational

Substances

Acetyltransferases
E1A-Associated p300 Protein
EP300 protein, human
Curcumin
Lysine