On the Value of Homology Models for Virtual Screening: Discovering hCXCR3 Antagonists by Pharmacophore-Based and Structure-Based Approaches

Human chemokine receptor CXCR3 (hCXCR3) antagonists have
potential
therapeutic applications as antivirus, antitumor, and anti-inflammatory
agents. A novel virtual screening protocol, which combines pharmacophore-based
and structure-based approaches, was proposed. A three-dimensional
QSAR pharmacophore model and a structure-based docking model were
built to virtually screen for hCXCR3 antagonists. The hCXCR3 antagonist
binding site was constructed by homology modeling and molecular dynamics
(MD) simulation. By combining the structure-based and ligand-based
screenings results, 95% of the compounds satisfied either pharmacophore
or docking score criteria and would be chosen as hits if the union
of the two searches was taken. The false negative rates were 15% for
the pharmacophore model, 14% for the homology model, and 5% for the
combined model. Therefore, the consistency of the pharmacophore model
and the structural binding model is 219/273 = 80%. The hit rate for
the virtual screening protocol is 273/286 = 95%. This work demonstrated
that the quality of both the pharmacophore model and homology model
can be measured by the consistency of the two models, and the false
negatives in virtual screening can be reduced by combining two virtual
screening approaches.