Mukherjee Abhisek, Cuanalo-Contreras Karina, Sood Abha, Soto Claudio
Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, University of Texas Health Science at Houston, Houston, TX, 77030, USA.
The Department of Chemistry and Biochemistry, Georgia Southern University, USA.
Biochem Biophys Rep. 2022 Aug 12;31:101311. doi: 10.1016/j.bbrep.2022.101311. eCollection 2022 Sep.
Calcineurin (CaN) is a calcium/calmodulin-dependent serine/threonine phosphatase with a crucial role in cellular homeostasis. It is also the target of the Food and Drug Administration (FDA) approved immunosuppressant drugs FK506 and cyclosporine A. Recent work from our group and others indicated that an uncontrolled increase in CaN activity causes synaptic dysfunction and neuronal death in various models of neurodegenerative diseases associated with calcium dysregulation. Furthermore, pharmacological normalization of CaN activity can prevent disease progression in animal models. However, none of the FDA-approved CaN inhibitors bind CaN directly, leading to adverse side effects. The development of direct CaN inhibitors is required to reduce off-target effects, but its highly conserved active site and similar mechanism of action with other protein serine/threonine phosphatases impose a significant challenge. In this work, we developed a novel pharmacophore model to screen for CaN-specific inhibitors. Then, we performed a virtual screen for molecules having the pharmacophore model. We also show that the molecules identified in this screen can inhibit CaN with a low micromolar IC. Interestingly, the inhibitors identified from the screen do not inhibit phosphoprotein phosphatase 2A, a member of the serine/threonine phosphatase family that shares 43% sequence identity with the CaN active site. The pharmacophore model that we developed and validated in this work may help to accelerate the development of specific CaN inhibitors.
钙调神经磷酸酶（CaN）是一种钙/钙调蛋白依赖性丝氨酸/苏氨酸磷酸酶，在细胞内稳态中起关键作用。它也是美国食品药品监督管理局（FDA）批准的免疫抑制剂药物FK506和环孢素A的作用靶点。我们团队和其他团队最近的研究表明，在与钙调节异常相关的各种神经退行性疾病模型中，CaN活性不受控制地增加会导致突触功能障碍和神经元死亡。此外，CaN活性的药理学正常化可以预防动物模型中的疾病进展。然而，FDA批准的CaN抑制剂均不直接与CaN结合，从而导致不良副作用。需要开发直接的CaN抑制剂以减少脱靶效应，但其高度保守的活性位点以及与其他蛋白质丝氨酸/苏氨酸磷酸酶相似的作用机制带来了重大挑战。在这项工作中，我们开发了一种新型药效团模型来筛选CaN特异性抑制剂。然后，我们对具有该药效团模型的分子进行了虚拟筛选。我们还表明，在此筛选中鉴定出的分子可以低微摩尔浓度的半数抑制浓度（IC）抑制CaN。有趣的是，从筛选中鉴定出的抑制剂不会抑制丝氨酸/苏氨酸磷酸酶家族的成员——蛋白磷酸酶2A，该酶与CaN活性位点具有43%的序列同一性。我们在这项工作中开发并验证的药效团模型可能有助于加速特异性CaN抑制剂的开发。
