Cytosporone E analogues as BRD4 inhibitors for cancer treatment: molecular docking and molecular dynamic investigations

Makki, Alaa A.; Ibraheem, Walaa; Alzain, Abdulrahim A.

doi:10.1080/07391102.2023.2167122

Cited by 2 publications

(1 citation statement)

References 59 publications

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“…Similarly, all four lead compounds showed a stable RMSF with negligible fluctuation in the regions of both NBDs. Previous MD simulation studies demonstrated that fluctuations on the order of 1-3 Å can be indicative of stable docking for bimolecular systems [64,65]; however, in the case of larger proteins like ABCB1, a slightly larger fluctuation (4-5 Å) in RMSD is also acceptable [43]. Prior MD simulations of substrates in comparison with inhibitors of ABCB1 showed more fluctuation with the substrates in the RMSF of the nucleotide-binding region as compared to inhibitors [43].…”

Section: Discussionmentioning

confidence: 99%

Molecular Modeling Studies to Probe the Binding Hypothesis of Novel Lead Compounds against Multidrug Resistance Protein ABCB1

Cheema,

Linton,

Jabeen

2024

Biomolecules

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The expression of drug efflux pump ABCB1/P-glycoprotein (P-gp), a transmembrane protein belonging to the ATP-binding cassette superfamily, is a leading cause of multidrug resistance (MDR). We previously curated a dataset of structurally diverse and selective inhibitors of ABCB1 to develop a pharmacophore model that was used to identify four novel compounds, which we showed to be potent and efficacious inhibitors of ABCB1. Here, we dock the inhibitors into a model structure of the human transporter and use molecular dynamics (MD) simulations to report the conformational dynamics of human ABCB1 induced by the binding of the inhibitors. The binding hypotheses are compared to the wider curated dataset and those previously reported in the literature. Protein–ligand interactions and MD simulations are in good agreement and, combined with LipE profiling, statistical and pharmacokinetic analyses, are indicative of potent and selective inhibition of ABCB1.

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