title: Designing New Kinase Inhibitor Derivatives as Therapeutics Against Common Complex Diseases: Structural Basis of Microtubule Affinity-Regulating Kinase 4 (MARK4) Inhibition.
abstract: Drug development for common complex diseases is in need of new molecular entities and actionable drug targets. MAP/microtubule affinity-regulating kinase 4 (MARK4) is associated with numerous diseases such as neurodegenerative disorders, obesity, cancer, and type 2 diabetes. Understanding the structural basis of ligands' (inhibitors) and substrates' binding to MARK4 is crucial to design new kinase inhibitors for therapeutic purposes. This study reports new observations on docking three well-known kinase inhibitors in the kinase domain of MARK4 variants and the calculated binding affinity. These variants of MARK4 are named as MARK4-F1 (59 N-terminal residues along with kinase domain) and MARK4-F2 (kinase domain of MARK4). We additionally performed molecular dynamics (MD) simulation and fluorescence binding studies to calculate the actual binding affinity of kinase inhibitors, BX-912, BX-795, and OTSSP167 (hydrochloride) for the MARK4. Docking analyses revealed that ligands bind in the large hydrophobic cavity of the kinase domain of MARK4 through several hydrophobic and hydrogen-bonded interactions. Simulations suggested that OTSSP167 (hydrochloride) is forming a stable complex, and hence the best inhibitor of MARK4. Intrinsic fluorescence of MARK4 was significantly quenched by addition of ligands, indicating their potential binding to MARK4. A lower KD value of MARK4 with OTSSP167 (hydrochloride) suggested that it is a better interacting partner than BX-912 and BX-795. These data form a basis for designing novel and potent OTSSP167 (hydrochloride) derivatives as therapeutic candidates against common complex diseases. The inhibitors designed as such might possibly suppress the growth of tumor-forming cells and be potentially applied for treatment of a wide range of human cancers as well.
authors.affiliation: 1 Center for Interdisciplinary Research in Basic Sciences , Jamia Millia Islamia, Jamia Nagar, New Delhi, India .
authors.forename: Farha
authors.initials: F
authors.lastname: Naz
authors.affiliation: 2 Department of Chemistry, Durban University of Technology , Durban, South Africa .
authors.forename: Mohd
authors.initials: M
authors.lastname: Shahbaaz
authors.affiliation: 2 Department of Chemistry, Durban University of Technology , Durban, South Africa .
authors.forename: Krishna
authors.initials: K
authors.lastname: Bisetty
authors.affiliation: 1 Center for Interdisciplinary Research in Basic Sciences , Jamia Millia Islamia, Jamia Nagar, New Delhi, India .
authors.forename: Asimul
authors.initials: A
authors.lastname: Islam
authors.affiliation: 1 Center for Interdisciplinary Research in Basic Sciences , Jamia Millia Islamia, Jamia Nagar, New Delhi, India .
authors.forename: Faizan
authors.initials: F
authors.lastname: Ahmad
authors.affiliation: 1 Center for Interdisciplinary Research in Basic Sciences , Jamia Millia Islamia, Jamia Nagar, New Delhi, India .
authors.forename: Md Imtaiyaz
authors.initials: MI
authors.lastname: Hassan
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013050:Spectrometry, Fluorescence / Q000379:methods; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; C483047:MARK4 protein, human; D017346:Protein Serine-Threonine Kinases