Using Pharmacophore Models To Gain Insight into Structural Binding and Virtual Screening: An Application Study with CDK2 and Human DHFR

Citations Over TimeTop 10% of 2006 papers

Abstract

This study provides results from two case studies involving the application of the HypoGenRefine algorithm within Catalyst for the automated generation of excluded volume from ligand information alone. A limitation of pharmacophore feature hypothesis alone is that activity prediction is based purely on the presence and arrangement of pharmacophoric features; steric effects remained unaccounted. Recently reported studies have illustrated the usefulness of combining excluded volumes to the pharmacophore models. In general, these excluded volumes attempt to penalize molecules occupying steric regions that are not occupied by active molecules. The HypoGenRefine algorithm in Catalyst accounts for steric effects on activity, based on the targeted addition of excluded volume features to the pharmacophores. The automated inclusion of excluded volumes to pharmacophore models has been applied to two systems: CDK2 and human DHFR. These studies are used as examples to illustrate how ligands could bind in the protein active site with respect to allowed and disallowed binding regions. Additionally, automated refinement of the pharmacophore with these excluded volume features provides a more selective model to reduce false positives and a better enrichment rate in virtual screening.

Related Papers

• → Using Pharmacophore Models To Gain Insight into Structural Binding and Virtual Screening: An Application Study with CDK2 and Human DHFR(2006)48 cited
• → The integration of pharmacophore-based 3D QSAR modeling and virtual screening in safety profiling: A case study to identify antagonistic activities against adenosine receptor, A2A, using 1,897 known drugs(2019)30 cited
• → Pharmacophore Modelling as a Virtual Screening Tool for the Discovery of Small Molecule Protein-protein Interaction Inhibitors(2012)27 cited
• → QSAR Analysis of Indole Analogues as Monoamine Oxidase Inhibitors(1996)37 cited
• → Identification of potent anti-immunogenic agents through virtual screening, 3D-QSAR studies, and in vitro experiments(2023)1 cited