Application of Computational Methods to the Design of Fatty Acid Amide Hydrolase (FAAH) Inhibitors Based on a Carbamic Template Structure

Computer-aided approaches are widely used in modern medicinal chemistry to improve the efficiency of the discovery phase. Fatty acid amide hydrolase (FAAH) is a key component of the endocannabinoid system and a potential drug target for several therapeutic applications. During the past decade, different chemical classes of inhibitors, with different mechanisms of action, had been developed. Among them, alkyl carbamic acid biphenyl-3-yl esters represent a prototypical class of active site-directed inhibitors, which allowed detailed pharmacological characterization of FAAH inhibition. Both ligand- and structure-based drug design approaches have been applied to rationalize structure-activity relationships and to drive the optimization of the inhibitory potency for this class of compounds. In this chapter, we review our contribution to the discovery and optimization of therapeutically promising FAAH inhibitors, based on a carbamic template structure, which block FAAH in an irreversible manner exerting analgesic, anti-inflammatory and anxiolytic effects in animal models. The peculiar catalytic mechanism of FAAH, and the covalent interaction with carbamate-based inhibitors, prompted the application of different computer-aided tools, ranging from ligand-based approaches to docking procedures and quantum mechanics/molecular mechanics (QM/MM) hybrid techniques. Latest advancements in the field are also reported. Content: Copyright Page iv Chapter 1 - Application of Computational Methods to the Design of Fatty Acid Amide Hydrolase (FAAH) Inhibitors Based on a Carbamic Template Structure Pages 1-26 Alessio Lodola, Silvia Rivara, Marco Mor Recent theoretical and computational advances for modeling protein–ligand binding affinities Pages 27-80 Emilio Gallicchio, Ronald M. Levy Chpater 3 - Hybrid Schemes Based on Quantum Mechanics/Molecular Mechanics Simulations: Goals to Success, Problems, and Perspectives Pages 81-142 Silvia Ferrer, Javier Ruiz-Pernía, Sergio Martí, Vicent Moliner, Iñaki Tuñón, Juan Bertrán, Juan Andrés Chapter 4 - Exploring Membrane and Protein Dynamics with Dissipative Particle Dynamics Pages 143-182 Gernot Guigas, Diana Morozova, Matthias Weiss Coarse-grained Representation of Protein Flexibility. Foundations, Successes, and Shortcomings Pages 183-215 Modesto Orozco, Laura Orellana, Adam Hospital, Athi N. Naganathan, Agustí Emperador, Oliver Carrillo, J.L. Gelpí Chapter 6 - Recent Advances in the Molecular Modeling of Estrogen Receptor-Mediated Toxicity Pages 217-251 Ivanka Tsakovska, Ilza Pajeva, Petko Alov, Andrew Worth Chapter 7 - Multiscale computational methods for mapping conformational ensembles of G-protein-coupled receptors Pages 253-280 Nagarajan Vaidehi, Supriyo Bhattacharya Chapter 8 - Advances in Implicit Models of Water Solvent to Compute Conformational Free Energy and Molecular Dynamics of Proteins at Constant pH Pages 281-322 Yury N. Vorobjev Author Index Pages 323-340 Subject Index Pages 341-351

Published continuously since 1944, the Advances in Protein Chemistry and Structural Biology serial has been a continuous, essential resource for protein chemists. Covering reviews of methodology and research in all aspects of protein chemistry, including purification/expression, proteomics, modeling and structural determination and design, each volume brings forth new information about protocols and analysis of proteins while presenting the most recent findings from leading experts in a broad range of protein-related topics. This volume features articles on Computational Chemistry methods in Structural Biology.

Essential resource for protein chemists This volume features articles on Computational Chemistry methods in Structural Biology

Published continuously since 1944, the Advances in Protein Chemistry and Structural Biology serial has been a continuous, essential resource for protein chemists. Covering reviews of methodology and research in all aspects of protein chemistry, including purification/expression, proteomics, modeling and structural determination and design, each volume brings forth new information about protocols and analysis of proteins while presenting the most recent findings from leading experts in a broad range of protein-related topics. This volume features articles on Computational Chemistry methods in Structural Biology. Essential resource for protein chemists. This volume features articles on Computational Chemistry methods in Structural Biology Covering reviews of methodology and research in various aspects of protein chemistry, including purification/expression, proteomics, modeling and structural determination and design, this title brings forth information about protocols and analysis of proteins while presenting the findings from experts in a range of protein-related topics.