Title:A Practical Guide to Molecular Docking and Homology Modelling for Medicinal Chemists
Volume: 17
Issue: 18
Author(s): Anna E. Lohning*, Stephan M. Levonis, Billy Williams-Noonan and Stephanie S. Schweiker
Affiliation:
- Faculty of Health Sciences and Medicine, Bond University, Gold Coast, 4229, Queensland,Australia
Keywords:
Molecular docking, Homology modelling, Medicinal chemistry, Lead identification.
Abstract: Elucidating details of the relationship between molecular structure and a particular biological
end point is essential for successful, rational drug discovery. Molecular docking is a widely accepted
tool for lead identification however, navigating the intricacies of the software can be daunting. Our objective
was therefore to provide a step-by-step guide for those interested in incorporating contemporary
basic molecular docking and homology modelling into their design strategy. Three molecular docking
programs, AutoDock4, SwissDock and Surflex-Dock, were compared in the context of a case study
where a set of steroidal and non-steroidal ligands were docked into the human androgen receptor (hAR)
using both rigid and flexible target atoms. Metrics for comparison included how well each program predicted
the X-ray structure orientation via root mean square deviation (rmsd), predicting known actives
via ligand ranking and comparison to biological data where available. Benchmarking metrics were discussed
in terms of identifying accurate and reliable results. For cases where no three dimensional structure
exists, we provided a practical example for creating a homology model using Swiss-Model. Results
showed an rmsd between X-ray ligands from wild-type and mutant receptors and docked poses were
4.15Å and 0.83Å (SwissDock), 2.69Å and 8.80Å (AutoDock4) and 0.39Å and 0.71Å (Surflex-Dock)
respectively. Surflex-Dock performed consistently well in pose prediction (less than 2Å) while Auto-
Dock4 predicted known active non-steroidal antiandrogens most accurately. Introducing flexibility into
target atoms produced the largest degree of change in ligand ranking in Surflex-Dock. We produced a
viable homology model of the P2X1 purireceptor for subsequent docking analysis.
