Identification of Nonpeptide CCR5 Receptor Agonists by Structure-based Virtual Screening

Abstract

A three-dimensional model of the chemokine receptor CCR5 has been built to fulfill structural peculiarities of its alpha-helix bundle and to distinguish known CCR5 antagonists from randomly chosen drug-like decoys. In silico screening of a library of 1.6 million commercially available compounds against the CCR5 model by sequential filters (drug-likeness, 2-D pharmacophore, 3-D docking, scaffold clustering) yielded a hit list of 59 compounds, out of which 10 exhibited a detectable binding affinity to the CCR5 receptor. Unexpectedly, most binders tested in a functional assay were shown to be agonists of the CCR5 receptor. A follow-up database query based on similarity to the most potent binders identified three new CCR5 agonists. Despite a moderate affinity of all nonpeptide ligands for the CCR5 receptor, one of the agonists was shown to promote efficient receptor internalization, which is a process therapeutically favorable for protection against HIV-1 infection.

Ligand and structure-based methodologies for the prediction of the activity of G protein-coupled receptor ligands

“…Similarly, using molecular databases spiked with known binders, a number of studies based on combinations of different scoring functions (such as Gold [68], Dock [69], CScore (Tripos), Fresno [70], Score [71], FlexX [72], and PMF [66]) have demonstrated the applicability of molecular docking at GPCR models to virtual screening [9,10,73]. In agreement with the expectations set by these studies, a variety of docking programs and scoring functions have been successfully applied to the discovery of novel ligands for a plethora of GPCRs, including neurorokinin [74,75], adrenergic [76], chemokine [75,77], dopamine [75], serotonin [75,78], cannabinoid [79], and free fatty acid receptors [80], among others.…”

Identification of a low–molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice

“…The virtual screening strategy was performed using this model and by focusing on the specificity interaction patch between the BDNF N-terminal region and the TrkB-d5 domain ( Figure 1). The Bioinfo-DB database of 1.6 million commercially available drug-like compounds (30) was first filtered for lead-like properties (31), including notably predicted water solubility and blood-brain barrier permeation, to afford 78,045 compounds. Preliminary docking studies of the BDNF terminal epitope (H 1 SDPAR 6 ) with various docking algorithms indicated that the FlexX program (32) was particularly well suited for docking in the TrkB specificity site.…”

Oligomeric-Induced Activity by Thienyl Pyrimidine Compounds Traps Prion Infectivity

“…The structural coordinates of human PrP C (HuPrP C ) (1QLZ, Protein Data Bank) were used for molecular modeling studies of the PrP and the search for a putative binding site conserved in both PrP C and PrP Sc isoforms. The in silico screening was performed using the Bioinfo chemical library (Kellenberger et al, 2007) and the Gold 2.0 Software (Jones and Thornton, 1997;Verdonk et al, 2003). Candidate molecules were visualized at the conserved binding site using the Insight II Accelrys software with the Silicon Graphics SGI 02 R10000 workstation.…”