Rational design and preliminary validation of novel BU10119 analogs for the management of SSRI refractory depression

Abstract

Kappa Opioid Receptor and Mu Opioid Receptor Antagonism has been shown to be useful in the treatment of SSRI Refractory Depression. BU10119 is a dual Kappa Opioid Receptor and Mu Opioid Receptor antagonist that is used in this study as a lead. The crystallographic structures of both the opioid receptors were obtained from Protein Data Banks 4DJH and 4DKL. The Virtual Screening Approach and the de novo Design Approach are performed in this study. Virtual Screening Approach involves a Ligand Based Drug Design, while the de novo Design Approach involves a Structure Based Drug Design. During the Virtual Screening Approach, BU10119 was superimposed onto antagonists for both receptors to identify the optimal conformers. Consensus Pharmacophores were created for each antagonist using LigandScout®. During the de novo Approach, different seed structures were created derived from the optimal BU10119 spatial arrangement and allowed to grow within the ligand binding pocket of the respective receptor. This approach resulted in a total of six molecular seed structures of high affinity to the Kappa Opioid Receptor, and limited activity to the Mu Opioid Receptor. These six molecular seed structures had diverse structures from the novel BU10119 molecule. This study proved valuable in exploring the maximum ligand binding pocket area through the creation of a pharmacophore during the Virtual Screening Approach. The de novo Approach was used as further validation to this study in as a more innovative approach.