This book provides an updated review of the latest advances experienced in recent years in the field of molecular modelling and simulation of biomolecular recognition, with particular emphasis towards the development of efficient strategies in structure-based drug design. The main aims of the book are to provide a detailed description of the physico-chemical principles that underlie the ligand-receptor interaction, to describe the methodological basis of computational tools to elucidate the molecular features that modulate the ligand-receptor interaction and to highlight the impact of the methodological innovations in drug design. The publication covers a wide range of topics relevant to the development of drugs and provides, in a single volume, a comprehensive description of the major methodological strategies available for rational drug discovery. There are two main features that make this book unique. Firstly, the contents are oriented to provide a physico-chemical basis of the methodological tools described in the book, which capture the essential features inherent to the recognition between ligands and their receptors. Secondly, standard formalisms widely accepted in the pharmaceutical and medicinal chemistry arena are presented with an updated review of the latest advances experienced in the field. Overall, the contents of the book provide the reader with clear guidelines to calibrate the performance of the current methodologies used in drug design. The book will be essential reading for academic and industrial researchers working in modelling of biomolecular systems and drug discovery.

F Javier Luque is a Professor at the Department of Physical Chemistry in the University of Barcelona, and leader of the Computational Biology and Drug design group at the Institute of Biomedicine. He received his BA degree in Chemistry from the Universitat Autonoma de Barcelona in 1985 and his PhD in Chemistry from the Universitat Autonoma de Barcelona in 1989. He joined the Departament de Fisicoquimica in 1986, and was appointed Associate Professor in Physical Chemistry in 1992, and in 2003, he was promoted to the position of Full Professor. His research interests are the theoretical representation of chemical reactivity and the modeling of solvation effects, the simulation of biochemical systems, with particular emphasis in the dynamical description of the structure-function relationships in proteins, and in the interaction between ligand and macromolecular receptors, specially orientated to structure-based drug discovery.

Preface; recognition of ligands by macromolecular targets; thermodynamics of ligand binding; continuum solvation in biomolecular systems; bioavailability prediction at early drug discovery stages: in vitro assays and simple physicochemical rules; computational strategies in drug design; molecular descriptors for database mining; pharmacophore models in drug design; docking and virtual screening; binding free energy calculations and scoring in small-molecule docking; COMparative BINding Energy (COMBINE) analysis as a structure-based 3D-QSAR method; accounting for target flexibility during ligand-receptor docking; enhanced sampling methods in drug design; exploring diversity of drug target sites; expanding the target space: druggability assessment; computational strategies and challenges for targeting protein-protein interactions with small molecules; case studies; using molecular simulations and metadynamics to predict binding free energies and kinetics; the case of COX and CDK2; Computer-assisted design of drug-like synthetic libraries; index