Development of a novel pharmacophore model to screen specific inhibitors for the serine-threonine protein phosphatase calcineurin

Abhisek Mukherjee; Karina Cuanalo-Contreras; Abha Sood; Claudio Soto

doi:10.1016/j.bbrep.2022.101311

Development of a novel pharmacophore model to screen specific inhibitors for the serine-threonine protein phosphatase calcineurin

Biochem Biophys Rep. 2022 Aug 12:31:101311. doi: 10.1016/j.bbrep.2022.101311. eCollection 2022 Sep.

Authors

Abhisek Mukherjee¹, Karina Cuanalo-Contreras¹, Abha Sood², Claudio Soto¹

Affiliations

¹ 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.
² The Department of Chemistry and Biochemistry, Georgia Southern University, USA.

Abstract

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 IC₅₀. 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.