Design and identification of Kappa Opioid receptor modulators for the treatment of addiction

Abstract

Drug addiction may be defined as the uncontrollable urge to make use of certain types of drugs in spite of their serious adverse effects. The Kappa Opioid Receptor (K-OR) was originally considered a target for analgesia but recent studies have shown that it is also associated with natural addiction control mechanisms. The objective of this project is to use Salvinorin A as the lead molecule to the design of novel drugs which modulate the K-OR, through de novo and virtual screening (VS) techniques. The PDB (protein data bank) crystallographic deposition 4DJH describing the bound co ordinates of small molecule JDTic and the K-OR was selected for this study. All molecular modelling was done in Sybyl®-X V2.1. The small molecule JDTic was extracted from its LBP. Salvinorin A molecule was computationally docked into the K-OR_LBP. The optimally binding Salvinorin A conformers from each positionally diverse group were identified through conformational analysis. For the structure based drug design, two seed structures identical for all four positionally diverse conformers were created by maintaining the structural moieties, which based on the 2D topology map were essential for binding. de novo molecules were generated in LigBuilder® v1.2. These novel structures were divided into various families having different pharmacophores and filtered in accordance to Lipinski’s rule of five. For the in silico ligand based drug design, a consensus pharmacophore was generated for each of the optimal conformers and these were submitted into ZINCPharmer® for analog identification. A protomol was modeled in Sybyl®-X V2.1 and the Lipinski Rule Compliant hits identified were docked into this protomol and ranked by affinity. 132 and 31 Lipinski Rule Compliant molecules were identified through de novo and virtual screening respectively. The molecules with the highest affinity are recommended for further validation.