González-Durruthy Michael, Concu Riccardo, Osmari Vendrame Laura F, Ortiz Martins Mirkos, Zanella Ivana, Ruso Juan Manuel, Dias Soeiro Cordeiro Maria Natália
LAQV-REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal.
Soft Matter and Molecular Biophysics Group, Department of Applied Physics, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain.
Curr Top Med Chem. 2023;23(1):62-75. doi: 10.2174/1568026622666220303115102.
Herein, molecular docking approaches and DFT ab initio simulations were combined for the first time, to study the key interactions of cyclodextrins (CDs: α-CD, β-CD, and γ-CD) family with potential pharmacological relevance and the multidrug resistance P-gp protein toward efficient drug-delivery applications. The treatment of neurological disorders and cancer therapy where the multiple drug-resistance phenomenon mediated by the P-gp protein constitutes the fundamental cause of unsuccessful therapies.
To understand more about the CD docking mechanism and the P-gp.
In order to achieve the main goal, the computational docking process was used. The observed docking-mechanism of the CDs on the P-gp was fundamentally based on hybrid backbone/side-chain hydrophobic interactions,and also hybrid electrostatic/side-chain interactions of the CD-ligands' OHmotifs with acceptor and donor characteristics, which might theoretically cause local perturbations in the TMD/P-gp inter-residues network, influencing ligand extrusion through the blood-brain barrier. P-gp residues were conformationally favored. Despite the structural differences, all the cyclodextrins exhibit very close Gibbs free binding energy values (or affinity) by the P-gp binding site (transmembrane domains - TMDs).
The obtained theoretical docking-mechanism of the CDs on the P-gp was fundamentally based on hybrid backbone/side-chain hydrophobic interactions, and also hybrid electrostatic/side-chain interactions of the OH-motifs of the CD-ligands with acceptor and donor properties which theoretically could induce allosteric local-perturbations in the TMDs-inter-residues network of P-gp modulating to the CD-ligand extrusion from the blood-brain-barrier (or cancer cells).
Finally, these theoretical results open new horizons for evaluating new nanotherapeutic drugs with potential pharmacological relevance for efficient drug-delivery applications and precision nanomedicine.
本文首次将分子对接方法与密度泛函理论从头算模拟相结合，以研究具有潜在药理学相关性的环糊精（CDs：α - CD、β - CD和γ - CD）家族与多药耐药P - gp蛋白之间的关键相互作用，以实现高效药物递送应用。在神经疾病治疗和癌症治疗中，P - gp蛋白介导的多药耐药现象是治疗失败的根本原因。
更深入了解CD对接机制和P - gp。
为实现主要目标，采用了计算对接过程。观察到的CDs在P - gp上的对接机制主要基于主链/侧链混合疏水相互作用，以及具有受体和供体特征的CD - 配体OH基序的静电/侧链混合相互作用，这在理论上可能导致跨膜结构域/TMDs间残基网络的局部扰动，影响配体通过血脑屏障的外排。P - gp残基在构象上是有利的。尽管结构存在差异，但所有环糊精通过P - gp结合位点（跨膜结构域 - TMDs）表现出非常接近的吉布斯自由结合能值（或亲和力）。
所获得的CDs在P - gp上的理论对接机制主要基于主链/侧链混合疏水相互作用，以及具有受体和供体特性的CD - 配体OH基序的静电/侧链混合相互作用，理论上这可能会在P - gp的TMDs间残基网络中诱导变构局部扰动，从而调节CD - 配体从血脑屏障（或癌细胞）的外排。
最后，这些理论结果为评估具有潜在药理学相关性的新型纳米治疗药物以实现高效药物递送应用和精准纳米医学开辟了新视野。
