Designing new kinase inhibitor derivatives as therapeutics against common complex diseases : structural basis of microtubule afﬁnity-regulating kinase 4 (MARK4) inhibition
Hassan, Md. Imtaiyaz
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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 pur-poses. 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 addi-tionally 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 (hy-drochloride) 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.
Naz, F. et al. 2015. Designing new kinase inhibitor derivatives as therapeutics against common complex diseases : structural basis of microtubule afﬁnity-regulating kinase 4 (MARK4) inhibition. OMICS: A Journal of Integrative Biology, 19(11): 700-711.