67
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Advances and Challenges in Protein-Ligand Docking

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Molecular docking is a widely-used computational tool for the study of molecular recognition, which aims to predict the binding mode and binding affinity of a complex formed by two or more constituent molecules with known structures. An important type of molecular docking is protein-ligand docking because of its therapeutic applications in modern structure-based drug design. Here, we review the recent advances of protein flexibility, ligand sampling, and scoring functions—the three important aspects in protein-ligand docking. Challenges and possible future directions are discussed in the Conclusion.

          Related collections

          Most cited references 124

          • Record: found
          • Abstract: found
          • Article: not found

          A fast flexible docking method using an incremental construction algorithm.

          We present an automatic method for docking organic ligands into protein binding sites. The method can be used in the design process of specific protein ligands. It combines an appropriate model of the physico-chemical properties of the docked molecules with efficient methods for sampling the conformational space of the ligand. If the ligand is flexible, it can adopt a large variety of different conformations. Each such minimum in conformational space presents a potential candidate for the conformation of the ligand in the complexed state. Our docking method samples the conformation space of the ligand on the basis of a discrete model and uses a tree-search technique for placing the ligand incrementally into the active site. For placing the first fragment of the ligand into the protein, we use hashing techniques adapted from computer vision. The incremental construction algorithm is based on a greedy strategy combined with efficient methods for overlap detection and for the search of new interactions. We present results on 19 complexes of which the binding geometry has been crystallographically determined. All considered ligands are docked in at most three minutes on a current workstation. The experimentally observed binding mode of the ligand is reproduced with 0.5 to 1.2 A rms deviation. It is almost always found among the highest-ranking conformations computed.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Benchmarking sets for molecular docking.

            Ligand enrichment among top-ranking hits is a key metric of molecular docking. To avoid bias, decoys should resemble ligands physically, so that enrichment is not simply a separation of gross features, yet be chemically distinct from them, so that they are unlikely to be binders. We have assembled a directory of useful decoys (DUD), with 2950 ligands for 40 different targets. Every ligand has 36 decoy molecules that are physically similar but topologically distinct, leading to a database of 98,266 compounds. For most targets, enrichment was at least half a log better with uncorrected databases such as the MDDR than with DUD, evidence of bias in the former. These calculations also allowed 40x40 cross-docking, where the enrichments of each ligand set could be compared for all 40 targets, enabling a specificity metric for the docking screens. DUD is freely available online as a benchmarking set for docking at http://blaster.docking.org/dud/.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              A critical assessment of docking programs and scoring functions.

              Docking is a computational technique that samples conformations of small molecules in protein binding sites; scoring functions are used to assess which of these conformations best complements the protein binding site. An evaluation of 10 docking programs and 37 scoring functions was conducted against eight proteins of seven protein types for three tasks: binding mode prediction, virtual screening for lead identification, and rank-ordering by affinity for lead optimization. All of the docking programs were able to generate ligand conformations similar to crystallographically determined protein/ligand complex structures for at least one of the targets. However, scoring functions were less successful at distinguishing the crystallographic conformation from the set of docked poses. Docking programs identified active compounds from a pharmaceutically relevant pool of decoy compounds; however, no single program performed well for all of the targets. For prediction of compound affinity, none of the docking programs or scoring functions made a useful prediction of ligand binding affinity.
                Bookmark

                Author and article information

                Journal
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                Molecular Diversity Preservation International (MDPI)
                1422-0067
                2010
                18 August 2010
                : 11
                : 8
                : 3016-3034
                Affiliations
                [1 ] Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA; Email: huangshe@ 123456missouri.edu
                [2 ] Department of Physics and Astronomy, University of Missouri, Columbia, MO 65211, USA
                [3 ] Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA
                [4 ] Informatics Institute, University of Missouri, Columbia, MO 65211, USA
                Author notes
                *Author to whom correspondence should be addressed; E-Mail: zoux@ 123456missouri.edu ; Tel.: +1-573-882-6045; Fax: +1-573-884-4232.
                Article
                ijms-11-03016
                10.3390/ijms11083016
                2996748
                21152288
                © 2010 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.

                This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                Categories
                Review

                Comments

                Comment on this article