Novel Method for Generating Structure-Based Pharmacophores Using Energetic Analysis

TLDR

The study presents a novel method for generating energetically optimized, structure‑based pharmacophores to accelerate in silico screening. The method integrates Glide XP energy terms with pharmacophore perception and database screening, producing energy‑optimized hypotheses from 30 crystal structures and benchmarking against contact‑based, Glide SP docking, and 2D fingerprint approaches. Compared to contact‑based, Glide SP docking, and 2D fingerprint methods, the new approach delivers higher enrichment and greater diversity of actives, with docking alone achieving the most high‑enrichment cases and the combined strategy balancing enrichment and diversity.

Abstract

We describe a novel method to develop energetically optimized, structure-based pharmacophores for use in rapid in silico screening. The method combines pharmacophore perception and database screening with protein-ligand energetic terms computed by the Glide XP scoring function to rank the importance of pharmacophore features. We derive energy-optimized pharmacophore hypotheses for 30 pharmaceutically relevant crystal structures and screen a database to assess the enrichment of active compounds. The method is compared to three other approaches: (1) pharmacophore hypotheses derived from a systematic assessment of receptor-ligand contacts, (2) Glide SP docking, and (3) 2D ligand fingerprint similarity. The method developed here shows better enrichments than the other three methods and yields a greater diversity of actives than the contact-based pharmacophores or the 2D ligand similarity. Docking produces the most cases (28/30) with enrichments greater than 10.0 in the top 1% of the database and on average produces the greatest diversity of active molecules. The combination of energy terms from a structure-based analysis with the speed of a ligand-based pharmacophore search results in a method that leverages the strengths of both approaches to produce high enrichments with a good diversity of active molecules.