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

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.

The BH3-mimetic obatoclax reduces HIF-1α levels and HIF-1 transcriptional activity and sensitizes hypoxic colon adenocarcinoma cells to 5-fluorouracil

“…One such agent is obatoclax (OBX), a synthetic indolylprodigiosin derivative that was shown to bind to Bcl-2, Bcl-xL, Bcl-w and Mcl-1 [19][20][21]. Preclinical studies have shown that OBX is effective as a single agent against a broad range of cancer cell lines and xenografts [22] and that it synergizes with a number of cytotoxic and targeted anticancer agents [23][24][25][26][27][28][29].…”

Complex disruption effect of natural polyphenols on Bcl-2-Bax: molecular dynamics simulation and essential dynamics study

“…The structures of antiapoptotic protein (Bcl-2, Bcl-xL, and Mcl-1) consist primarily of two central hydrophobic helices surrounded by amphipathic helices (Petros, Olejniczak, & Fesik, 2004;Day et al, 2005). The binding groove is formed mainly by the α2, α 3, α 4, and α 5 helices (Acoca, Cui, Shore, & Purisima, 2011) (Figure 1). Ku et al (2011) found that the 31-mer Bax peptide (residues 52-82) and the 36-mer Bax peptide (residues 49-84) bind Bcl-2 nearly with equal potency.…”

“…All the previous studies regarding the inhibition of Bcl-2 were mainly targeted to the Bax-unbound form of Bcl-2 (Acoca et al, 2011;Mohammadi et al, 2014;Saxena et al, 2013) in our knowledge. It is well defined that the interaction of bcl-2 and bax is mainly dependent on few residues of both proteins.…”

3-Thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile (S1) derivatives as pan-Bcl-2-inhibitors of Bcl-2, Bcl-xL and Mcl-1

“…22 Additionally, a broader p4 pocket in Mcl-1 than that in Bcl-2 has been revealed by a molecular dynamics study. 15 These studies suggested that the p4 pocket has less contribution to Mcl-1 binding. In the present study, however, we found binding affinities to Mcl-1 were progressively improved accompanied with increased p4 occupation.…”

“…Previous studies have reported that Bcl-2 and Mcl-1 show differences in the structure of their p4 pockets. 15 When we tried to occupy the p4, an optimization path should be carefully designed to resolve differences of the p4 between Bcl-2 and Mcl-1 without losing either one. At the outset, we aimed to maintain the binding mode with R263 in Mcl-1 and R146 in Bcl-2 constant since the key hydrogen bound was formed in this region.…”