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Binding site hotspot map of PI3Kα and mTOR in the presence of selective and dual ATP-competitive inhibitors.
Nunes Azevedo, Francisca Fernanda; Freitas de Sousa, Francisca Joseli; Santos de Oliveira, Francisco Lucas; Vieira Carletti, Jaqueline; Zanatta, Geancarlo.
Afiliación
  • Nunes Azevedo FF; Postgraduate Programme in Biochemistry, Department of Biochemistry at Federal, University of Ceará, Fortaleza, Ceará, Brazil.
  • Freitas de Sousa FJ; Postgraduate Programme in Biochemistry, Department of Biochemistry at Federal, University of Ceará, Fortaleza, Ceará, Brazil.
  • Santos de Oliveira FL; Department of Physics at Federal, University of Ceará, Fortaleza, Ceará, Brazil.
  • Vieira Carletti J; Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Ceará, Brazil.
  • Zanatta G; Postgraduate Programme in Biochemistry, Department of Biochemistry at Federal, University of Ceará, Fortaleza, Ceará, Brazil.
J Biomol Struct Dyn ; 41(3): 1085-1097, 2023 02.
Article en En | MEDLINE | ID: mdl-34913837
The PI3K/Akt/mTOR signaling pathway plays a pivotal role in cellular metabolism, growth and survival. PI3Kα hyperactivation impairs downstream signaling, including mTOR regulation, and are linked to poor prognosis and refractory cancer treatment. To support multi-target drug discovery, we took advantage from existing PI3Kα and mTOR crystallographic structures to map similarities and differences in their ATP-binding pockets in the presence of selective or dual inhibitors. Molecular dynamics and MM/PBSA calculations were employed to study the binding profile and identify the relative contribution of binding site residues. Our analysis showed that while varying parameters of solute and solvent dielectric constant interfered in the absolute binding free energy, it had no effect in the relative per residue contribution. In all complexes, the most important interactions were observed within 3-3.5 Å from inhibitors, responding for ∼75-100% of the total calculated interaction energy. While closest residues are essential for the strength of the binding of all ligands, more distant residues seem to have a larger impact on the binding of the dual inhibitor, as observed for PI3Kα residues Phe934, Lys802 and Asp805 and, mTOR residues Leu2192, Phe2358, Leu2354, Lys2187 and Tyr2225. A detailed description of individual residue contribution in the presence of selective or dual inhibitors is provided as an effort to improve the understanding of molecular mechanisms controlling multi-target inhibition. This work provides key information to support further studies seeking the rational design of potent PI3K/mTOR dual inhibitors for cancer treatment.Communicated by Ramaswamy H. Sarma.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfatidilinositol 3-Quinasas / Serina-Treonina Quinasas TOR Idioma: En Revista: J Biomol Struct Dyn Año: 2023 Tipo del documento: Article País de afiliación: Brasil Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfatidilinositol 3-Quinasas / Serina-Treonina Quinasas TOR Idioma: En Revista: J Biomol Struct Dyn Año: 2023 Tipo del documento: Article País de afiliación: Brasil Pais de publicación: Reino Unido