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In Silico Pharmacology

, 6:1 | Cite as

In silico quest of selective naphthyl-based CREBBP bromodomain inhibitor

  • Raju Dash
  • Sarmistha Mitra
  • Md. Arifuzzaman
  • S. M. Zahid Hosen
Original Research
  • 29 Downloads

Abstract

The reader proteins like bromodomains have recently gained increased attentions in the area of epigenetic drug discovery, as they are the potent regulators in gene transcription process. Among the other bromodomains, cAMP response element-binding protein (CREB) binding protein or CREBBP bomodomain involved in various cancer progressions and therefore, efforts to develop specific inhibitors of CREBBP bomodomain are of clinical value. In this study, we tried to identify selective CREBBP bromodomain inhibitor, which was accomplished by using molecular docking, free energy calculation and molecular dynamics (MD) simulation studies, considering a series of naphthyl based compounds. The docking procedure was validated by comparing root mean square deviations (RMSDs) of crystallographic complex to docked complex. Favorable electrostatic interactions with the Arg1173 side chain were considered to attain selectivity for CREBBP bromodomain over other human bromodomain subfamilies. We found that naphthyl-based compounds have greater binding affinities towards the CREBBP bromodomain, and formed non-bonded interactions with various side chain residues that are important for bromodomain inhibition. From detailed investigation by induced fit docking, compound 31 was found to have favorable electrostatic interactions with the Arg1173 side chain by forming conventional hydrogen bonds. This result was further confirmed by analyzing hydrogen bond occupancy and bonding distance during the molecular dynamics simulation. We believe that these findings offer useful insight for the designing of target specific new bromodomain inhibitor and also promote further structure guided synthesis of analogues for identification of potent CREBBP bromodomain inhibitors as well as detailed in vitro and in vivo analyses.

Keywords

Bromodomain CREBBP Selectivity In silico 

Abbreviations

BET

Bromo and extra terminal

cAMP

Cyclic adenosine monophosphate

CREB

Cyclic-AMP response element-binding protein

CHARMm

Chemistry at HARvard macromolecular mechanics

CREBBP

cAMP response element-binding brotein (CREB) binding protein

EMM

Molecular mechanics energies

EP300

Adenoviral E1A binding protein of 300 kDa

GNP

Non-polar solvation (GNP)

GSGB

Solvation model for polar solvation

HTVS

High throughout virtual screening

Kcal/mol

Kilocalorie per mol

MD

Molecular dynamics

MM

Molecular mechanics

MM-GBSA

Molecular mechanics-generalised born and surface area

NAMD

Nanoscale molecular dynamics

PME

Particle mesh Ewald

Rg

Radius of gyration

RMSD

Root mean square deviation

RMSF

Root mean square fluctuation

SAR

Structure activity relationship

SGB

Surface generalized born

TIP3P

The transferable intermolecular potential3 points

XP

Extra precision

Notes

Author contributions

RD and SMZH conceived and designed the study. RD and SM preformed the experiments, prepared the figures, and wrote the initial draft. MA and SMZH analyzed the data, guided and supported in the preparation of manuscript. All authors have read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no competing interests.

Supplementary material

40203_2018_38_MOESM1_ESM.doc (1.8 mb)
Supplementary material 1 (DOC 1893 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Raju Dash
    • 1
    • 2
  • Sarmistha Mitra
    • 3
  • Md. Arifuzzaman
    • 2
  • S. M. Zahid Hosen
    • 1
  1. 1.Molecular Modeling and Drug Design Laboratory, Pharmacology Research DivisionBangladesh Council of Scientific and Industrial ResearchChittagongBangladesh
  2. 2.Department of Biochemistry and BiotechnologyUniversity of Science and TechnologyChittagongBangladesh
  3. 3.Department of PharmacyUniversity of ChittagongChittagongBangladesh

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