Comparison and Druggability Prediction of Protein–Ligand Binding Sites from Pharmacophore-Annotated Cavity Shapes

Abstract

Estimating the pairwise similarity of protein−ligand binding sites is a fast and efficient way of predicting cross-reactivity and putative side effects of drug candidates. Among the many tools available, threedimensional (3D) alignment-dependent methods are usually slow and based on simplified representations of binding site atoms or surfaces. On the other hand, fast and efficient alignment-free methods have recently been described but suffer from a lack of interpretability. We herewith present a novel binding site description (VolSite), coupled to an alignment and comparison tool (Shaper) combining the speed of alignment-free methods with the interpretability of alignment-dependent approaches. It is based on the comparison of negative images of binding cavities encoding both shape and pharmacophoric properties at regularly spaced grid points. Shaper approximates the resulting molecular shape with a smooth Gaussian function and aligns protein binding sites by optimizing their volume overlap. Volsite and Shaper were successfully applied to compare protein− ligand binding sites and to predict their structural druggability.

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“…In this study, Discovery Studio program 42 was used for pharmacophore modeling and the five molecules from the previous step were entered to the Hip Hop generator at Discovery Studio program and gave two hypothetical pharmacophores (pictures not shown).…”

Insights into the structure and inhibition ofGiardia intestinalisarginine deiminase: homology modeling, docking, and molecular dynamics studies

“…All possible binding sites were analyzed using VolSite program (Desaphy, Azdimousa, Kellenberger, & Rognan, 2012) , which predicted the druggability by comparing the GiADI possible binding sites with a collection of validated druggable binding site targets. The cavity of the catalytic site was the only with the characteristics to bind a small molecule ligand.…”

Pharmacophore Modeling: Methods and Applications

“…These approaches generally are not capable of generating an alignment of a matching molecule to the model, nor is there necessarily any guarantee that such an alignment is feasible. Nonetheless, pharmacophore similarity measures naturally integrate with other fingerprint-based methods [68] and, in addition to their utility in virtual screening, are useful for other purposes such as assessing binding site similarity [69,70] and "target fishing" for novel targets of known ligands [58].…”