Role of lisinopril in the therapeutic management of cardiovascular disease by targeting microtubule affinity regulating kinase 4: molecular docking and molecular dynamics simulation approaches

Abstract

Cardiovascular diseases (CVDs) are a major cause of premature adult death. Various factors contribute to the development of CVDs, such as atherosclerosis leading to myocardial infarction (MI), and compromised cardiac function after MI leads to chronic heart failure with systemic health complications and a high mortality rate. Microtubule detyrosination has rapidly evolved as an essential mechanism to regulate cardiomyocyte contractility. Microtubule affinity regulating kinase 4 (MARK4) regulates cardiomyocyte contractility in a way that it promotes phosphorylation of microtubule-associated protein 4, thereby facilitating the access of vasohibin 2—a tubulin carboxypeptidase—to microtubules for the detyrosination of α-tubulin. Lisinopril, a drug belonging to the class of angiotensin-converting enzyme inhibitors, is used to treat high blood pressure. This is also used to treat heart failure, which plays a vital role in improving the survival rate post-heart attack. In this study, we will evaluate the MARK4 inhibitory potential of lisinopril employing molecular docking and molecular dynamics (MD) simulation approaches. Molecular docking analysis suggested that lisinopril binds to MARK4 with a significant binding affinity forming interactions with functionally essential residues of MARK4. Additionally, MD simulation deciphered the structural dynamics and stability of the MARK4–lisinopril complex. The findings of MD studies established that minimal structural deviations are observed during simulation, affirming the stability of the MARK4–lisinopril complex. Altogether, this study demonstrates lisinopril’s crucial role in the therapeutic management of CVD by targeting MARK4.

Communicated by Ramaswamy H. Sarma

Keywords:

• Myocardial infarction
• kinases
• cardiovascular disease
• molecular docking
• molecular dynamics simulation

Disclosure statement

No potential conflict of interest was reported by the authors.

Authors’ contributions

Conceptualization, A.A., G.M.A., A.L.B., and M.S.; methodology, A.A., N.M.A., M.S., A.B.M., D.D.G., and D.A.; software, A.A., D.D.G., and G.M.A., validation; A.A., G.M.A., and N.M.A.; formal analysis, A.A., D.D.G., G.M.A., and A.B.M.; writing—original draft and preparation, A.A., A.L.B., and N.M.A.; writing—review and editing, A.A., D.D.G., and G.M.A.; visualization, A.A. and G.M.A.; project administration, A.A., A.L.B., and N.M.A.; funding acquisition, A.A., A.L.B., and N.M.A.

Additional information

Funding

The authors are thankful to the Deanship of Scientific Research, King Khalid University, Abha, Saudi Arabia, for financially supporting this work through the Large Research Group Program under grant number (RGP.2/137/1443). This research work was funded by the Institutional Fund Projects under grant no. (IFPDP-205-22). Therefore, authors gratefully acknowledge technical and financial support from Ministry of Education and Deanship of Scientific Research (DSR), King Abdulaziz University, Jeddah, Saudi Arabia.