Identification of Therapeutic Agents Targeting Mitogen-Activated Protein Kinase 14 in the Treatment and Management of Asthma

Abstract

ABSTRACT: Mitogen-activated protein Kinase 14 (MAPK14) plays a pivotal role in the pathophysiology of asthma, influencing inflammation, airway remodeling, and bronchial hyperresponsiveness, highlighting its significance as a potential therapeutic target in asthma management. This study aimed to identify the inhibitory compounds from a small library of small molecule drugs curated from the DrugBank. We conducted a comprehensive exploration of the protein structure, cavity detection, molecular docking, ADMET predictions, and functional assays pertinent to lead molecules and MAPK14. Through protein structure homology modeling, the MAPK14 model exhibited exemplary quality, supported by high GMQE (0.90) and QMEANDisCo (0.82 ± 0.05) scores. Cavity detection highlighted prominent features, guiding subsequent molecular docking studies. Notably, Cobicistat emerged as a potential inhibitor, displaying strong binding affinity (-8.6 kcal/mol) across multiple binding pockets on MAPK14. ADMET predictions underscored its drug-like properties, while cytotoxicity assays on normal lung cells revealed its benign nature. Further investigations elucidated Cobicistat's inhibitory effect on MAPK14 expression and activity, validating its therapeutic potential for asthma treatment. Enzyme inhibition assay provided mechanistic insights, indicating Cobicistat's ability to modulate MAPK14 activity, thus positioning it as a promising therapeutic candidate for targeting MAPK14-associated diseases such as asthma. This comprehensive study underscores Cobicistat's multifaceted potential in therapeutic interventions, substantiating its candidacy for further validation.