High end GPCR design: crafted ligand design and druggability analysis using protein structure, lipophilic hotspots and explicit water networks

ABSTRACT:

Purpose

G Protein-Coupled Receptors (GPCRs) are a large family of therapeutically important proteins and as diverse X-ray structures become available it is increasingly possible to leverage structural information for rational drug design. We present herein approaches that use explicit water networks combined with energetic surveys of the binding site (GRID), providing an enhanced druggability and ligand design approach, with structural understanding of ligand binding, including a ‘magic’ methyl and binding site mutations, and a fast new approach to generate and score waters.

Methods

The GRID program was used to identify lipophilic and hydrogen bonding hotspots. Explicit full water networks were generated and scored for (pseudo)apo structures and ligand-protein complexes u

SUBMITTER: Mason J 

PROVIDER: S-EPMC4796210 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature