10.1021/acs.jcim.5b00265.s001
Ming Kuang
Ming
Kuang
Jingwei Zhou
Jingwei
Zhou
Laiyou Wang
Laiyou
Wang
Zhihong Liu
Zhihong
Liu
Jiao Guo
Jiao
Guo
Ruibo Wu
Ruibo
Wu
Binding Kinetics versus Affinities in BRD4 Inhibition
American Chemical Society
2015
JQ
inhibitor binding kinetics
BRD 4 InhibitionBromodomains
acetylated lysine substrate
MD
BRD 4
binding pocket size
IC
QM
2015-09-28 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Binding_Kinetics_versus_Affinities_in_BRD4_Inhibition/2127679
Bromodomains
(BRDs) are protein modules that selectively recognize
histones as a “reader” by binding to an acetylated lysine
substrate. The human BRD4 has emerged as a promising drug target for
a number of disease pathways, and several potent BRD inhibitors have
been discovered experimentally recently. However, the detailed inhibition
mechanism especially for the inhibitor binding kinetics is not clear.
Herein, by employing classical molecular dynamics (MD) and state-of-the-art
density functional QM/MM MD simulations, the dynamic characteristics
of ZA-loop in BRD4 are revealed. And then the correlation between
binding pocket size and ZA-loop motion is elucidated. Moreover, our
simulations found that the compound (−)-JQ1 could be accommodated
reasonably in thermodynamics whereas it is infeasible in binding kinetics
against BRD4. Its racemate (+)-JQ1 proved to be both thermodynamically
reasonable and kinetically achievable against BRD4, which could explain
the previous experimental results that (+)-JQ1 shows a high inhibitory
effect toward BRD4 (IC<sub>50</sub> is 77 nM) while (−)-JQ1
is inactive (>10 μM). Furthermore, the L92/L94/Y97 in the
ZA-loop
and Asn140 in the BC-loop are identified to be critical residues in
(+)-JQ1 binding/releasing kinetics. All these findings shed light
on further selective inhibitor design toward BRD family, by exploiting
the non-negligible ligand binding kinetics features and flexible ZA-loop
motions of BRD, instead of only the static ligand–protein binding
affinity.