Binding mode analyses of NAP derivatives as mu opioid receptor selective ligands through docking studies and molecular dynamics simulation

Abstract

Mu opioid receptor selective antagonists are highly desirable because of their utility as pharmacological probes for receptor characterization and functional studies. Furthermore, the mu opioid receptors act as an important target in drug abuse and addiction treatment. Previously, we reported NAP as a novel lead compound with high selectivity and affinity towards the mu opioid receptor. Based on NAP, we have synthesized its derivatives and further characterized their binding affinities and selectivity towards the receptor. NMP and NGP were identified as the two most selective MOR ligands among NAP derivatives. In the present study, molecular modeling methods were applied to assess the dual binding modes of NAP derivatives, particularly on NMP and NGP, in three opioid receptors, in order to analyze the effects of structural modifications on the pyridyl ring of NAP on the binding affinity and selectivity. The results indicated that the steric hindrance, electrostatic, and hydrophobic effects caused by the substituents on the pyridyl ring of NAP contributed complimentarily on the binding affinity and selectivity of NAP derivatives to three opioid receptors. Analyses of these contributions provided insights on future design of more potent and selective mu opioid receptor ligands.

Keywords: Binding affinity; Dual binding modes; Molecular modeling; NAP derivatives; Opioid receptors; Selectivity.

Figure 1

The chemical structures of NAP (a), NMP (b), and NGP (c). The chemical structures with atom notation were derived from the complexes after molecular dynamics simulations.

Figure 1

The chemical structures of NAP (a), NMP (b), and NGP (c). The chemical structures with atom notation were derived from the complexes after molecular dynamics simulations.

Figure 2

NMP conformation (yellow balls and sticks) in MOR ^{site B} (a), KOR ^{site B} (b), and DOR ^{site A} (c) with highest CHEM-PLP and HINT scores from docking studies.

Figure 3

NGP conformation (white balls and sticks) in MOR ^siteA (a), KOR ^{site A} (b), and DOR ^{site B} (c) with highest CHEM-PLP and HINT scores from docking studies.

Figure 4

The root-mean-square-deviation (rmsd) of the protein backbone atoms of the six complexes relative to the respective starting structures.

Figure 5

Binding modes of MOR^{site A}-NMP (a) and MOR^{site B}-NGP (b) complexes with key residues in the binding pocket after 10 ns MD simulations.

Figure 6

Binding modes of KOR^{site A}-NMP (a) and KOR^{site B}-NGP (b) complexes with key residues in the binding pocket after 10 ns MD simulations.

Figure 7

Binding modes of DOR^{site B}-NMP (a) and DOR^{site A}-NGP (b) complexes with key residues in the binding pocket after 10 ns MD simulations.