Zhijun Wu - Towards a Universal Mu-Agonist Template for Alignment Modeling of Opioid Ligands

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      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.

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