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Binding mode of Pyridoclax to Myeloid cell leukemia-1 (Mcl-1) revealed by Nuclear Magnetic Resonance Spectroscopy, Docking and Molecular Dynamics Approaches

Abstract : Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 family proteins. Its amplification is one of the most frequent genetic aberrations found in human cancers. Pyridoclax, a promising BH3 mimetic inhibitor, interacts directly with Mcl-1 and induces massive apoptosis at a concentration of 15 µM in combination with anti-Bcl-xL strategies in chemo-resistant ovarian cancer cell lines. In this study, a combined experimental and theoretical approach was used to investigate the binding mode of Pyridoclax to Mcl-1. The representative poses generated from dynamics simulations compared with NMR data revealed: (i) Pyridoclax bound to P1 and P2 pockets of Mcl-1 BH3 binding groove through its styryl and methyl groups establishing mainly hydrophobic contacts, (ii) one of the ending pyridines interacts through electrostatic interaction with K234 side chain, a negatively charged residue present only in this position in Mcl-1.
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https://hal-normandie-univ.archives-ouvertes.fr/hal-02330946
Contributor : Madeleine Roux-Merlin <>
Submitted on : Thursday, October 24, 2019 - 11:10:25 AM
Last modification on : Saturday, September 26, 2020 - 11:44:12 PM

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Asma Bourafai Aziez, Muriel Sebban, M. Benabderrahmane, B. Marekha, C. Denis, et al.. Binding mode of Pyridoclax to Myeloid cell leukemia-1 (Mcl-1) revealed by Nuclear Magnetic Resonance Spectroscopy, Docking and Molecular Dynamics Approaches. Journal of Biomolecular Structure and Dynamics, Taylor & Francis: STM, Behavioural Science and Public Health Titles, 2019, (in press). ⟨10.1080/07391102.2019.1680434⟩. ⟨hal-02330946⟩

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