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.

Design, Synthesis, and Biological Evaluation of the Third Generation 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4′-pyridyl)carboxamido]morphinan (NAP) Derivatives as μ/κ Opioid Receptor Dual Selective Ligands

“…44 Meanwhile, a molecular dynamics simulation study of NMP in the MOR, DOR, and KOR showed that the 3′-methyl group on the pyridyl ring may reinforce the π – π stacking interaction between the aromatic pyridyl ring of NMP and W318 7.35 of the MOR, which resulted in the high selectivity of NMP to the MOR over the DOR and KOR. 58 Further modeling study results indicated that the characteristics of the substituents on the 3′ position of pyridyl ring of NAP derivatives, such as steric hindrance, electrostatic, and hydrophobic effects, may have signiffcant effect on the binding affinity and selectivity of NAP derivatives to the three opioid receptors. 58 Therefore, in designing the third generation NAP derivatives, substitutions with different electronic, bulky, steric, and hydrophobic properties were introduced at the 3′ position of pyridyl ring (Figure 2).…”

“…NMP (17-cyclopropylmethyl-3,14 β -dihydroxy-4,5 α -epoxy-6 β -{[4′-(3′-methylpyridyl)]carboxamido}morphinan), a second generation NAP derivative, had improved pharmaco logical properties compared to NAP since it not only acted as a peripherally selective MOR antagonist but also improved motility of the gastrointestinal tract in vivo. 57a58 Further molecular modeling studies showed that the methyl group at 3′ position on the pyridyl group could reinforce the interactions between NMP and the “address” region of the MOR. 58 On the basis of these previous study results, we sought to further explore the influence on binding affinity of 3′ position on the pyridyl ring of NAP to opioid receptors based on the “message–address” concept.…”

“…57a58 Further molecular modeling studies showed that the methyl group at 3′ position on the pyridyl group could reinforce the interactions between NMP and the “address” region of the MOR. 58 On the basis of these previous study results, we sought to further explore the influence on binding affinity of 3′ position on the pyridyl ring of NAP to opioid receptors based on the “message–address” concept. 57a58 Thus, we designed, synthesized, and biologically evaluated a series of new compounds as the third generation NAP derivatives.…”

“…58 On the basis of these previous study results, we sought to further explore the influence on binding affinity of 3′ position on the pyridyl ring of NAP to opioid receptors based on the “message–address” concept. 57a58 Thus, we designed, synthesized, and biologically evaluated a series of new compounds as the third generation NAP derivatives. Two new compounds, NFP and NYP, were characterized in vitro and in vivo as opioid receptor antagonists.…”

Methylation Products of 6β-N-Heterocyclic Substituted Naltrexamine Derivatives as Potential Peripheral Opioid Receptor Modulators

“…The amide linker in dMNAP and dMNMP gave the pyridine ring enough flexibility to possibly interact with either one of the two “address” domains in the three opioid receptors, which had been defined in our previous studies. 63,64 Since one binding domain of the MOR, DOR and KOR is composed of highly conserved and negatively charged residues E 5.35 , D 5.35 , and D 5.35 , the quaternized pyridine ring in dMNAP and dMNMP seemed to prefer this domain in all three receptors due to the favorable electrostatic interactions between the compounds and the overall negatively charged binding loci (Figure 6).…”