Open challenges in structure-based virtual screening: Receptor modeling, target flexibility consideration and active site water molecules description.
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.
Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 183, 41125, Modena, Italy.
Francesca
F
Spyrakis
Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society (IBioBA-MPSP), Godoy Cruz 2390, C1425FQD, Buenos Aires, Argentina. Electronic address: cnc@cavasotto-lab.net.
Claudio N
CN
Cavasotto
D020134:Catalytic Domain; D003198:Computer Simulation; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000737:chemistry*; D014867:Water / Q000737:chemistry
D011956:Receptors, Cell Surface; D014867:Water
Active site water molecules; Homology modeling; Ligand docking; Protein flexibility; Structure-based drug discovery; Virtual screening