Institut de Chimie de Strasbourg, UMR7177, CNRS, Université de Strasbourg, F-67083, Strasbourg Cedex, France.
Kavli Institute for Brain & Mind University of California, San Diego La Jolla, CA, 92093, USA; Institut Pasteur, URA 2182, CNRS, F-75015, France; Collège de France, F-75005 Paris, France.
Mol Aspects Med. 2022 Apr;84:101044. doi: 10.1016/j.mam.2021.101044. Epub 2021 Oct 13.
We propose an extension and further development of the Monod-Wyman-Changeux model for allosteric transitions of regulatory proteins to brain communications and specifically to neurotransmitters receptors, with the nicotinic acetylcholine receptor (nAChR) as a model of ligand-gated ion channels. The present development offers an expression of the change of the gating isomerization constant caused by pharmacological ligand binding in terms of its value in the absence of ligands and several "modulation factors", which vary with orthosteric ligand binding (agonists/antagonists), allosteric ligand binding (positive allosteric modulators/negative allosteric modulators) and receptor desensitization. The new - explicit - formulation of such "modulation factors", provides expressions for the pharmacological attributes of potency, efficacy, and selectivity for the modulatory ligands (including endogenous neurotransmitters) in terms of their binding affinity for the active, resting, and desensitized states of the receptor. The current formulation provides ways to design neuroactive compounds with a controlled pharmacological profile, opening the field of computational neuro-pharmacology.
我们提出了一种对变构蛋白的莫诺德-怀曼-邱奇模型的扩展和进一步发展，将其应用于脑通讯，特别是神经递质受体，并以烟碱型乙酰胆碱受体（nAChR）作为配体门控离子通道的模型。目前的发展从没有配体存在时的数值及其几个“调节因子”的角度，用配体结合（激动剂/拮抗剂）、变构配体结合（正变构调节剂/负变构调节剂）和受体脱敏来表达药理学配体结合引起的门控异构化常数的变化。这种新的“调节因子”的明确表述，为调节性配体（包括内源性神经递质）的效力、效能和选择性的药理学属性提供了表述，其根据是它们与受体的活性、静息和脱敏状态的结合亲和力。目前的表述为设计具有可控药理学特征的神经活性化合物提供了途径，开辟了计算神经药理学的领域。
