Design and optimisation of μ-Opioid Agonists based on the PZM21 scaffold

Abstract

Currently existing opioids are associated with a number of dangerous and potentially fatal side effects including constipation and respiratory depression which has led to the development of safer and more effective therapeutic agents for pain management. The identification of PZM21 as a selective, potent and biased μ-opioid agonist shows its significant potential to be the leading member of a new class of analgesics which are more efficacious than traditional opioids without the typical concomitant adverse effects. This study uses the PZM21 scaffold, described by Manglik et al. in Nature in 2016 as the lead molecule to identify high affinity ligands using two design approaches; virtual screening and de novo design. Conformational analysis was carried out on the PZM21 scaffold. PZM21 was modelled and docked into the apo μ-opioid receptor which generated 20 different conformers. The optimal conformer was chosen by plotting ligand binding energy and ligand binding affinity against the conformer number and choosing the conformer which is most energetically feasible and exhibits highest affinity. In the first approach, the use of ligand-based virtual screening is based on the assumption that molecules with similar structures should exhibit similar effects on the same target. The ligand PZM21 was used as the template to generate a cohort of Lipinski rule complaint hits. The latter were docked into the protomol and the resultant 540 complaint molecules were ranked according to their their binding score. In the second approach, 4 seed structures were modelled based on the optimal conformer of PZM21 and growth was allowed within the pharmacophoric space to generate new molecules through de novo design. Molecular growth was restricted with a number of parameters to ensure penetration into the blood brain barrier. 428 de novo molecules were generated and separated based on the pharmacophoric similarity and ranked based on binding affinity. The optimal novel molecules that bind to the ligand binding pocket of the μ-opioid receptor with high affinity will be promoted for further optimisation, validation and in vitro testing.