Protein-Ligand Docking in Drug Design: Performance Assessment and Binding-Pose Selection
Main goal in drug discovery is the identification of drug-like compounds capable to modulate specific biological targets. Thus, the prediction of reliable binding poses of candidate ligands, through molecular docking simulations, represents a key step to be pursued in structure-based drug design (SBDD). Since the increasing number of resolved three-dimensional ligand-protein structures, together with the expansion of computational power and software development, the comprehensive and systematic use of experimental data can be proficiently employed to validate the docking performance. This allows to select and refine the protocol to adopt when predicting the binding pose of trial compounds in a target. Given the availability of multiple docking software, a comparative docking assessment in an early research stage represents a must-use step to minimize fails in molecular modeling. This chapter describes how to perform a docking assessment, using freely available tools, in a semiautomated fashion.
Key wordsDrug design Drug discovery Molecular docking Molecular modeling Docking assessment Structure-based drug design (SBDD)
F.B. thanks Prof. Garland R. Marshall (Washington University School of Medicine in St. Louis, MO) for supporting and funding the design and development of the Clusterizer-DockAccessor protocol; Dr. Chris M. W. Ho (Drug Design Methodologies, LLC, St. Louis, MO) and Ms. Mariama Jaiteh (Uppsala University, Uppsala, Sweden) for providing insightful comments.
- 5.Ballante F, Reddy DR, Zhou NJ et al (2017) Structural insights of SmKDAC8 inhibitors: targeting schistosoma epigenetics through a combined structure-based 3D QSAR, in vitro and synthesis strategy. Bioorg Med Chem 25(7):2105–2132. https://doi.org/10.1016/j.bmc.2017.02.020 CrossRefPubMedGoogle Scholar
- 6.Kubinyi H (1993) 3D QSAR in drug design. Volume 1: theory methods and applications. Three-dimensional quantitative structure activity relationships, Vol. 1. Springer, BerlinGoogle Scholar
- 8.Bursulaya BD, Totrov M, Abagyan R et al (2003) Comparative study of several algorithms for flexible ligand docking. J Comp Aided Molec Design 17(11):755–763. https://doi.org/10.1023/B:Jcam.0000017496.76572.6f CrossRefGoogle Scholar
- 17.Scharer K, Morgenthaler M, Paulini R et al (2005) Quantification of cation-pi interactions in protein-ligand complexes: crystal-structure analysis of Factor Xa bound to a quaternary ammonium ion ligand. Angew Chem Int Ed Eng 44(28):4400–4404. https://doi.org/10.1002/anie.200500883 CrossRefGoogle Scholar
- 19.Pinto DJ, Orwat MJ, Quan ML et al (2006) 1-[3-Aminobenzisoxazol-5’-yl]-3-trifluoromethyl-6-[2’-(3-(R)-hydroxy-N-pyrrolidin yl)methyl-[1,1’]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one (BMS-740808) a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa. Bioorg Med Chem Lett 16(15):4141–4147. https://doi.org/10.1016/j.bmcl.2006.02.069 CrossRefPubMedGoogle Scholar
- 23.The Open Babel Package. 2.4.1 http://openbabel.org. Accessed June 2017. edn.