Journal Article

Pseudoreceptor models in drug design: bridging ligand- and receptor-based virtual screening

Schneider, Gisbert, Tanrikulu, Yusuf

2008

Overview

Key Points During the early phase of drug discovery, in silico receptor-based and ligand-based strategies are used to find novel hits. Pseudoreceptor models link the concepts of both strategies for utilization in virtual screening and quantitative structure–activity relationship modelling. Essentially, pseudoreceptor models can provide an entry point for receptor-based approaches for cases in which high-resolution structures of targets are lacking. The methodology of pseudoreceptor model generation involves three fundamental tasks. First, the presumed key interaction sites (anchor points) of the ligand–receptor complex are defined; second, the core pseudoreceptor model is assembled around these hypotheses; and last, model coordinates are optimized to gain more accurate calculated binding energies in validation studies. Molecular alignment of selected known actives represents the foundation of pseudoreceptor generation. Various approaches can be used to ensure that an optimized model is generated, and these include the use of reference compounds for which their binding mode is experimentally supported; use of key interacting groups; and use of ligands with high-affinity. Models can be generated and refined using various methods, and six main categories are discussed: grid-based, isosurface-based, partition-based, atom-based, peptide-based and fragment-based. Various case studies of pseudoreceptor modelling for hit and lead finding are described, including a pseudoreceptor model of sweet-tasting molecules, de novo design of non-steroid oestrogen receptor antagonists and investigation of ligand binding to a cocaine receptor. Although pseudoreceptor models can be very useful, it is important to realize their limitations. Most importantly, they do not represent real macromolecular binding sites, but only a model that is generated from known ligands. Nevertheless, as long as these limitations are kept in mind, they are an important tool in the drug discovery process. Pseudoreceptor models can provide a valuable tool for drug design in cases where a high-resolution structure of the target is not available. This article reviews pseudoreceptor modelling techniques, presenting recent applications in hit and lead finding, and critically discusses the prerequisites, advantages and limitations of the various approaches. Rational drug design is based on explicit or implicit structure–activity relationship models. Typically, receptor-based or ligand-based strategies are pursued, depending on the information available about known ligands and the receptor structure. Pseudoreceptor models combine the advantages of these two strategies and represent a unifying concept for both receptor mapping and ligand matching. They can provide an entry point for structure-based modelling in drug discovery projects that lack a high-resolution structure of the target. Here, we review the field of pseudoreceptor modelling techniques along with recent hit and lead finding applications, and critically discuss prerequisites, advantages and limitations of the various approaches.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Animals / Biomedical and Life Sciences / Biomedicine / Biotechnology / Cancer Research / Computational biology / Computer Simulation / Drug Evaluation, Preclinical - methods / Drug Evaluation, Preclinical - trends / Drugs / Humans / Ligands / Medicinal Chemistry / Methods / Models, Molecular / Molecular Medicine / Pharmaceutical Preparations - chemical synthesis / Pharmacology/Toxicology / Product/Service Evaluations / Quantitative Structure-Activity Relationship / Radioligand assay / Receptors, Drug - chemistry / Receptors, Drug - metabolism / Receptors, G-Protein-Coupled - chemistry / Receptors, G-Protein-Coupled - metabolism / review-article