A combination of in silico and SAR studies to identify binding hot spots of Bcl-xL inhibitors

Abstract

To test if small and chemically diverse Bcl-xL inhibitors are likely to bind a single pocket, and to identify which pocket, we used a battery of computational and modeling approaches. We first checked that the large dataset of Bcl-xL inhibitors we built can actually fit to a universal pharmacophore. Then we defined the probable binding hot spots of interaction through comparison of crystal structures, as well as virtual fragment screening. Finally, new analogues of small polyphenol derivatives were synthesized to precisely probe a hydrogen bond suggested by docking experiments. Bcl-xL inhibition potency of these products confirmed the predicted binding mode. This combination of X-ray structure exploration, molecular modeling studies and medicinal chemistry supports that all these small Bcl-xL inhibitors occupy the same hot spot of interaction. The identification of this binding site should help the design and optimization of small PPI Bcl-xL inhibitors.

Structural revision of the Mcl-1 inhibitor MIM1: synthesis and biological studies on ovarian cancer cells with evaluation of designed analogues

“…Indeed, MIM1 caught our attention because we had already performed several studies on polyphenol-type derivatives as inhibitors of the antiapoptotic protein Bcl-xL. [37][38][39][40][41] During this study, we realised that the proposed MIM1 structure was not correct. Therefore, we performed extensive NMR, X-Ray crystallography and various physicochemical analyses to revise the structure of the MIM1 molecule from 1 to 2 (Fig.…”

Rational Drug Design of Antineoplastic Agents Using 3D-QSAR, Cheminformatic, and Virtual Screening Approaches

“…Bcl-2 inhibitors exhibit potent anticancer activity against breast cancer cells (MDA-231) and leukemia cells (HL-60) which overexpress Bcl-2 protein[85,86]. Several QSAR models have also been developed for this class of inhibitors[77,78,87] .Almerico and coworkers [78] developed a 3D-QSAR pharmacophore model of Bcl-xl inhibitors from the set of 42 biarylacylsulfonamides. This model was used to identify the structural factors, including an aromatic moiety, negative charge and hydrogen bond acceptor, that govern the activity of these derivatives.…”

Planejamento, síntese e avaliação do potencial antitumoral de compostos arilsulfonil-hidrazônicos

“…Interessante observar que o análogo sulfonamídico RPF105, contendo o substituinte terc-butil, apresentou atividade inferior em linhagem MCF-7, mostrando que, dependendo do substituinte no anel aromático, o grupo sulfonil-hidrazona pode ser mais favorável à atividade biológica em comparação a outros isósteros. Isto reforça o fato de que estudos de REA devem levar em conta todos os fatores estruturais das moléculas avaliadas, e não uma modificação molecular isoladamente (BARREIRO;FRAGA, 2008;LEVOIN et al, 2015;LOWINGER et al, 2002;PATRICK, 2013…”