Linagliptin and Empagliflozin Inhibit Microtubule Affinity Regulatory Kinase 4: Repurposing Anti-Diabetic Drugs in Neurodegenerative Disorders Using In Silico and In Vitro Approaches

Abstract

Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are significant public health burdens. Many studies have revealed the possibility of common pathophysiology between T2DM and AD. Thus, in recent years, studies deciphering the action mechanism of anti-diabetic drugs with their future use in AD and related pathologies are on high demand. Drug repurposing is a safe and effective approach owing to its low cost and time-saving attributes. Microtubule affinity regulating kinase 4 (MARK4) is a druggable target for various diseases and is found to be linked with AD and diabetes mellitus. MARK4 plays a vital role in energy metabolism and regulation and thus serves as an irrefutable target to treat T2DM. The present study was intended to identify the potent MARK4 inhibitors among FDA-approved anti-diabetic drugs. We performed structurebased virtual screening of FDA-approved drugs to identify the top hits against MARK4. We identified five FDA-approved drugs having an appreciable affinity and specificity toward the binding pocket of MARK4. Among these identified hits, two drugs, linagliptin, and empagliflozin, favorably bind to the MARK4 binding pocket, interacting with its critical residues and thus subjected to detailed analysis. All-atom detailed molecular dynamics (MD) simulations revealed the dynamics of binding of linagliptin and empagliflozin with MARK4. Kinase assay showed significant inhibition of MARK4 kinase activity in the presence of these drugs, implying them as potent MARK4 inhibitors. In conclusion, linagliptin and empagliflozin may be promising MARK4 inhibitors, which can further be exploited as potential lead molecules against MARK4-directed neurodegenerative diseases.

Interaction of Sp1 and Setd8 promotes vascular smooth muscle cells apoptosis by activating Mark4 in vascular calcification

“…The Marks contain four members of Mark1-4, which are located on human chromosomes 1, 11, 14 and 19, respectively, and play distinct physiological regulatory [ 36 ]. Numerous studies have shown that Mark4 is closely associated with the occurrence of diverse diseases, including cancer [ 13 ], Alzheimer’s disease [ 37 ], and cardiovascular disease [ 38 , 39 ]. In the current study, we found that the expression levels of all Marks except Mark3 was increased in high phosphorus-induced VSMCs, while the elevation of Mark4 was the most pronounced.…”

use of SGLT2 inhibitors in the treatment of cognitive disorders

“…Wykazano, że zahamowanie nadmiernej aktywacja kinazy MARK4 może zmniejszyć rozwój choroby Alzheimera oraz zahamować rozwój nowotworów. [26] Aktualnie oczekujemy na wyniki pilotażowego randomizowanego badania kontrolowanego (NCT03801642) przeprowadzanego przez University of Kansas Alzheimer's Disease Center oceniającego wpływ dapagliflozyny na pacjentów dorosłych z łagodną lub umiarkowaną chorobą Alzheimera. [27]…”

Preclinical Studies of Canagliflozin, a Sodium-Glucose Co-Transporter 2 Inhibitor, and Donepezil Combined Therapy in Alzheimer’s Disease

“…In addition, a wealth of evidence indicates a strong participation of SGLT2i in improving cognitive functions, by inhibiting AChE activity and increasing the acetylcholine levels [21][22][23][24]. Furthermore, these compounds improve peripheral insulin sensitivity, as well as brain signaling, which is impaired in the AD pathogenesis [25].…”