Computational Chemistry

Medicinal Chemistry Group

Molecular modeling is used to assess the role of structure in diverse bioactivity profiles; however, in the end all the hypotheses developed from models have to be tested or validated by chemical synthesis of the opioid ligands and through site-directed mutagenesis of selected residues in the receptor. The design, synthesis and testing of opioid peptide agonists and antagonists is crucial to investigating the physicochemical relationships involved in δ- and µ-opioid receptor activation (agonism) and non-activation or inhibition (antagonism).

Knowledge of the key elements that comprise the receptor binding site would permit application of computational modeling in a predictive mode; i.e., to eventually screen potential antagonist molecules for binding to δ- and µ-opioid receptors. Furthermore, specific computational analyses can estimate the penetration of compounds through the blood-brain barrier and their potential efficacies as clinically relevant drugs. These predictions can be validated using pharmacological assays. The techniques would serve as a tool to screen for drug-like compounds and could augment the chemical design process.

The breakdown of the contributions by different chemical descriptors is important to the design of opioid analogues in order to achieve improved biological properties. This information will be useful in design as well as in developing hypotheses for agonist and antagonist interactions with the δ-opioid receptors. A molecular modeling program provides for the direct and interactive visualization opioid ligands docking into receptors. The interaction between ligand and receptor is a highly complex mechanism involving not only the incoming opioid ligand and its receptor, but also the solvent, charge and dynamic motions of both molecules must be taken into account.

For more information on the Medicinal Chemistry Group’s computational chemistry research, see the following links.

• Accomplishments
• Conclusions

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