Publication Details (including relevant citation information):
Wu, Z. and V. Hruby (2016). "Towards a universal mu-agonist template for alignment modeling of opioid ligads." The 252nd ACS National Meeting, Philadelphia, PA.
Template alignment modeling (TAM) is a newly developed ligand-based modeling approach for drug design, where a rigid molecular template is applied that ligands of diverse structures are to be aligned with it. By doing so, it is possible to reveal clearly and effectively the structural features as well as the structural correlations among the diverse ligands. This modeling approach can also render insights for the structure-activity relationships (SARs) studies of ligands.
Opioid ligands are a large group of GPCR ligands with high structural diversity. And it has been a great challenge for medicinal chemists to recognize the potential structural correlations among the ligands, the critical information needed for new opioid drug design. Through TAM approach we previously proposed three receptor-subtype related pharmacophore models of opioid ligands, where morphine was used as the key template (PMID: 21488692). Although the models were quite helpful for us to understand better the complex SARs of opioid ligands, the scope and efficacy of the modeling were still limited, which was mainly attributed to the small size of morphine template. Therefore, establishment of a larger sized template for TAM modeling is highly desired in order for the improved applications on opioid ligands.
Herein, we wish to report the preliminary results of our recent efforts in establishing universal opioid ligand templates for TAM modeling. The current example illustrated is a mu-agonist specialized template, which was constructed and validated with a wide variety of mu-specific agonists, including both peptide and non-peptide ligands. Typical examples will be discussed regarding construction, validation, and potential applications of the template in opioid ligand SARs studies.