Molecular dynamics study of small molecule inhibitors of the Bcl-2 family

From National Research Council Canada

DOI	Resolve DOI: https://doi.org/10.1002/prot.23083
Author	Search for: Acoca, Stephane; Search for: Cui, Qizhi; Search for: Shore, Gordon C.; Search for: Purisima, Enrico O.
Format	Text, Article
Abstract	We carried out docking and molecular dynamics simulations on ABT-737 and obatoclax, which are inhibitors of the Bcl-2 family of proteins. We modeled the binding mode of ABT-737 with Bcl-x(L) , Bcl-2, and Mcl-1 and examined their dynamical behavior. We found that the binding of the chlorobiphenyl end of ABT-737 was quite stable across all three proteins. However, the phenylpiperazine linker group was dramatically more mobile in Mcl-1 compared to either Bcl-x(L) or Bcl-2. The S-phenyl group at the p4 binding site was well-anchored in Bcl-x(L) and Bcl-2 but was somewhat more mobile in Mcl-1 although the phenyl ring itself on average stayed close to the p4 binding site in Mcl-1. This greater mobility is likely due to the greater openness of the p3 and p4 binding sites on Mcl-1. The calculated binding free energies were consistent with the much weaker binding affinity of ABT-737 for Mcl-1. Obatoclax was predicted to bind at the p1 and p2 binding sites of Mcl-1 and the binding mode was quite stable during the molecular dynamics simulation with Mcl-1 wrapping around the molecule. The modeled binding mode suggests that obatoclax is able to inhibit all three proteins because it makes use of the p1 and p2 binding sites alone, which is a fairly narrow groove in all three proteins unlike the p4 binding site, which is much broader in Mcl-1.
Publication date	2011-09
In	Proteins : Structure, Function, and Bioinformatics 79, no. 9 (September 2011): 2624–2636.
Language	English
Peer reviewed	Yes
NRC publication	This is a non-NRC publication "Non-NRC publications" are publications authored by NRC employees prior to their employment by NRC.
NRC number	NRCC 53170
NPARC number	21268222
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Record identifier	a38d671f-2a54-41ba-8ab8-e4fe12cf9b4d
Record created	2013-06-05
Record modified	2020-04-21

Date modified:: 2024-04-20