Latest developments in molecular docking: 2010–2011 in review

Abstract

The aim of docking is to accurately predict the structure of a ligand within the constraints of a receptor binding site and to correctly estimate the strength of binding. We discuss, in detail, methodological developments that occurred in the docking field in 2010 and 2011, with a particular focus on the more difficult, and sometimes controversial, aspects of this promising computational discipline. The main developments in docking in this period, covered in this review, are receptor flexibility, solvation, fragment docking, postprocessing, docking into homology models, and docking comparisons. Several new, or at least newly invigorated, advances occurred in areas such as nonlinear scoring functions, using machine-learning approaches. This review is strongly focused on docking advances in the context of drug design, specifically in virtual screening and fragment-based drug design. Where appropriate, we refer readers to exemplar case studies.

Understanding the challenges of protein flexibility in drug design

“…In fact, the noise introduced by each extra conformation may obscure the additional information it provides, typically by generating false positives [66]. This problem highlights the need for clear guidelines to select the experimental structures that should compose the ensemble [24]. To this end, various selection strategies have been suggested [68], [82], [84]- [86], but no consensus has been reached.…”

“…Considering target flexibility has a direct impact on docking experiments, potentially leading to different results, and consequently having major implications for drug discovery [22], [23]. Therefore, protein flexibility has become a major goal in molecular docking, as acknowledged by several recent reviews [5], [24], [25]. Because of the diversity of docking methods accounting for protein flexibility, general classifications are useful to provide overviews of shared concepts and applications.…”

The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases—Part III: In-Silico Molecular Docking Investigations

“…These limitations stem, mostly, from the inability of the scoring functions in molecular docking algorithms to account for local and global macromolecular dynamics, in addition to inability to accurately predict covalent interactions and solvent accessibilities: (1) in most cases the protein is modeled as a rigid structure without flexibility; (2) solvation of the active/binding site and of the ligand is usually excluded; (3) free-energy estimation of protein-ligand complexes is largely ignored [357,361,362]. Molecular docking methodology, cavity definition and search algorithms, and thermodynamic scoring functions continue to improve, however [363].…”

In Vitro and Computational Assessment of Genotoxic Potential of Active Constituents Present in Three Medicinally Important Plant Extracts

“…It is based on the 3D structure of the target or ligand. In molecular docking which is ligand based, target site of a known inhibitor is used in order to get the structural information in as detail as possible (Yuriev and Ramsland, 2013).…”