期刊
MOLECULAR BIOSYSTEMS
卷 10, 期 7, 页码 1845-1868出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c3mb70591a
关键词
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资金
- Department of Biotechnology (Govt. of India) [BT/PR15118/BID/07/357/2011]
- Council of Scientific and Industrial Research [09/559/(0074)/2011/EMR-I]
Prostate cancer, the second most common form of cancer in adult males is generally treated using hormone therapy but the emergence of hormone refractory prostate cancer poses serious challenges to the existing therapeutic strategies. However, protein kinases are now currently identified as potent targets for treating cancer, and MARK4L, a Ser/Thr kinase in the Par-1 family, is one such kinase that is expressed primarily in the testis and is involved in the regulation of spermatid polarity during spermatogenesis. It is also associated with Wnt-induced prostate carcinogenesis, making it a promising target for the development of anti-cancer therapeutics as part of alternative therapies to counter prostate cancer. In the present work, we predicted the three dimensional structure for the kinase domain of MARK4 and analyzed its structural properties. The results illuminate the presence of the unusual DFG Asp-in/alpha C helix-out conformation along with the absence of an additional hydrophobic pocket adjacent to the ATP binding site in its inactive state. These structural features accentuate the need for new specific therapeutics against MARK4. Hence, a robust ligand-based pharmacophore model AARRR.9 was developed based on the three dimensional chemical features of 9-oxo-9H-acridin-10-yl derivatives which possess a high specificity towards MARK kinases. A pharmacophore based search identified six potent compounds with a better specificity and binding efficiency to MARK4 bearing stable interactions with key residues K88, A138, D199 and E106, thereby making them tough ATP competitors. The closure of the catalytic cleft observed in the ligand bound complexes and its independency to the movement of the T-loop makes them promising candidates in hampering the role of MARK4 in prostate cancer.
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