Issue 33, 2020

Deciphering the selectivity of inhibitor MKC9989 towards residue K907 in IRE1α; a multiscale in silico approach

Abstract

The selectivity of the ligand MKC9989, as inhibitor of the Inositol-Requiring Enzyme 1α (IRE1α) transmembrane kinase/ribonuclease protein, towards the residue K907 in the context of Schiff base formation, has been investigated by employing an array of in silico techniques including Multi-Conformation Continuum Electrostatics (MCCE) simulations, Quantum Mechanics/Molecular Mechanics (QM/MM) calculations, covalent docking, and Molecular Dynamics (MD) simulations. According to the MCCE results, K907 displays the lowest pKa value among all 23 lysine residues in IRE1α. The MMCE simulations also indicate a critical interaction between K907 and D885 within the hydrophobic pocket which increases significantly at low protein dielectric constants. The QM/MM calculations reveal a spontaneous proton transfer from K907 to D885, consistent with the low pKa value of K907. A Potential Energy Surface (PES) scan confirms the lack of energy barrier and transition state associated with this proton transfer reaction. Covalent docking and MD simulations verify that the protein pocket containing K907 can effectively stabilize the inhibitor by strong π–π and hydrogen bonding interactions. In addition, Radial Distribution Function (RDF) analysis shows that the imine group formed in the chemical reaction between MKC9989 and K907 is inaccessible to water molecules and thus the probability of imine hydrolysis is almost zero. The results of the current study explain the high selectivity of the MKC9989 inhibitor towards the K907 residue of IRE1α.

Graphical abstract: Deciphering the selectivity of inhibitor MKC9989 towards residue K907 in IRE1α; a multiscale in silico approach

Article information

Article type
Paper
Submitted
28 Feb 2020
Accepted
14 May 2020
First published
26 May 2020
This article is Open Access
Creative Commons BY license

RSC Adv., 2020,10, 19720-19729

Deciphering the selectivity of inhibitor MKC9989 towards residue K907 in IRE1α; a multiscale in silico approach

S. J. Mahdizadeh, A. Carlesso and L. A. Eriksson, RSC Adv., 2020, 10, 19720 DOI: 10.1039/D0RA01895C

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements