Molecular Modeling of Protein Kinases: Current Status and Challenges
Molecular modeling and virtual screening are currently among the main tools in kinase inhibitor design. In addition, molecular dynamics is actively used to study structural features and function of kinases. During the last 20 years, computational power ha
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Molecular Modeling of Protein Kinases: Current Status and Challenges Antti Poso
Contents 1 Introduction 2 Virtual Screening and Docking 3 MD Simulations 4 Allosteric Control of Kinases 5 Discussion References
Abstract Molecular modeling and virtual screening are currently among the main tools in kinase inhibitor design. In addition, molecular dynamics is actively used to study structural features and function of kinases. During the last 20 years, computational power has dramatically increased, and at the same time, algorithms have become more user-friendly. This has resulted in a situation where these powerful methods are more easily available for even larger groups of scientists. To effectively use computational methods, one should understand in great detail how protein kinases are functioning and how current protein kinase inhibitors interact with the kinase domain. This short review presents some of the main topics of kinase modeling, concentrating especially on proper selection and preparation of protein structure and general usage of MD simulations. Keywords Docking, Molecular dynamics, Structure-based drug design, Virtual screening
A. Poso (*) School of Pharmacy, University of Eastern Finland, Kuopio, Finland Department of Internal Medicine VIII, University Hospital Tübingen, Tübingen, Germany e-mail: antti.poso@uef.fi
A. Poso
1 Introduction One of the first molecular modeling studies dealing with protein kinases was published by Fry, Kuby, and Mildvan [1] in the mid-1980s. The authors used NMR NOE’s and molecular modeling to understand how MgATP interacts with rabbit muscle adenylate kinase. This study can be understood as a starting point for a great deal of and increasingly more active research on small molecule-kinase interactions. Surprisingly, we are still facing partially the same obstacles as Fry et al. some 35 years ago. In a highly simplified way, we are trying to understand structural properties of kinases and how kinase inhibitors are modifying these properties. The current main question is how kinase function and conformation effect upon the inhibitor binding are related to each other. Although the current paradigm in kinase drug design is to interfere the biological activity of kinase with small molecules, we do now understand that this inhibition cannot be modeled only by a simple docking experiment between a small drug-like molecule and the ATP-binding site of the target kinase. Instead, it is mandatory to study the whole kinase domain with solvent and, in many cases, with additional domains and interacting proteins. This chapter will deal with the molecular modeling of kinases. Although some structural biology data is also presented, I would warmly recommend the reader to study the excellent text by Röhm, Krämer, and Knapp in this book (Chap. XX) to begin with. Modeling is, after all, based on our knowledge of structural biology, and very little can be achieved without high-quality protein structures. In addition, protein kinases share several unique structural features, like hydrophobic sp
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