Identification of novel inhibitors of tropomyosin-related kinase A through the structure-based virtual screening with homology-modeled protein structure.
Tropomyosin-related kinase A (TrkA) is a promising target for the development of cancer and pain therapeutics. Here, we report the first successful example of the use of a structure-based virtual screening to identify novel TrkA inhibitors. The accuracy of the virtual screening was improved by introducing an accurate solvation free energy term into the original AutoDock scoring function. We applied a drug design protocol involving homology modeling, docking analysis of a large chemical library, and enzyme inhibition assays to identify six structurally diverse TrkA inhibitors with K(d) values ranging from 3 to 40 μM. The significant potencies and good physicochemical properties of these drug candidates strongly support their consideration in a development effort that would involve structure-activity relationship (SAR) studies to optimize the inhibitory activities. We also addressed the structural and energetic features associated with binding of the newly identified inhibitors in the ATP-binding site of TrkA. The results indicate that any structural modifications introduced for the purpose of enhancing the activity of TrkA inhibitors should maximize the attractive interactions within the ATP-binding site and simultaneously minimize the desolvation cost for complexation.
Department of Bioscience and Biotechnology, Sejong University, 98 Kunja-Dong, Kwangjin-Ku, Seoul 143-747, Korea. hspark@sejong.ac.kr
Hwangseo
H
Park
Okyung
O
Chi
Jinhee
J
Kim
Sungwoo
S
Hong
D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014584:User-Computer Interface
D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D000255:Adenosine Triphosphate; D011494:Protein Kinases; C041311:tropomyosin kinase