Journal
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Volume 583, Issue -, Pages 105-119Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2015.08.002
Keywords
Structure-based drug discovery; Homology modeling; Ligand docking; Virtual screening; Protein flexibility; Active site water molecules
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Funding
- Agencia Nacional de Promocion Cientifica y Tecnologica, Argentina [PICT-2011-2778]
- FOCEM-Mercosur [COF 03/11]
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Structure-based virtual screening is currently an established tool in drug lead discovery projects. Although in the last years the field saw an impressive progress in terms of algorithm development, computational performance, and retrospective and prospective applications in ligand identification, there are still long-standing challenges where further improvement is needed. In this review, we consider the conceptual frame, state-of-the-art and recent developments of three critical structural issues in structure-based drug lead discovery: the use of homology modeling to accurately model the binding site when no experimental structures are available, the necessity of accounting for the dynamics of intrinsically flexible systems as proteins, and the importance of considering active site water molecules in lead identification and optimization campaigns. (C) 2015 Elsevier Inc. All rights reserved.
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