A DFT and Semiempirical Model-Based Study of Opioid Receptor Affinity and Selectivity in a Group of Molecules with a Morphine Structural Core

Abstract

We report the results of a search for model-based relationships between mu, delta, and kappa opioid receptor binding affinity and molecular structure for a group of molecules having in common a morphine structural core. The wave functions and local reactivity indices were obtained at the ZINDO/1 and B3LYP/6-31G∗∗ levels of theory for comparison. New developments in the expression for the drug-receptor interaction energy expression allowed several local atomic reactivity indices to be included, such as local electronic chemical potential, local hardness, and local electrophilicity. These indices, together with a new proposal for the ordering of the independent variables, were incorporated in the statistical study. We found and discussed several statistically significant relationships for mu, delta, and kappa opioid receptor binding affinity at both levels of theory. Some of the new local reactivity indices incorporated in the theory appear in several equations for the first time in the history of model-based equations. Interaction pharmacophores were generated for mu, delta, and kappa receptors. We discuss possible differences regulating binding and selectivity in opioid receptor subtypes. This study, contrarily to the statistically backed ones, is able to provide a microscopic insight of the mechanisms involved in the binding process.

A Quantum-chemical Study of the Relationships Between Electronic Structure and Anti-proliferative Activity of Quinoxaline Derivatives on the HeLa Cell Line

“…Local Atomic Reactivity Indices and their physical meaning [44]. The Klopman-Peradejordi-Gómez (KPG) method is also discussed in many previous papers [30,35,36,38,39,42,[44][45][46]. From a conceptual perspective, the work presented here is a test of the hypothesis stating that the KPG model can provide a quantitative and formal relationship between the molecular structure and any biological activity.…”

“…From a conceptual perspective, the work presented here is a test of the hypothesis stating that the KPG model can provide a quantitative and formal relationship between the molecular structure and any biological activity. Nowadays, the KPG model produced excellent results in all its applications [35,44,[46][47][48][49][50][51][52][53].…”

Model-Based Quantum-Chemical Study of the Uptake of Some Polychlorinated Pollutant Compounds by Zucchini Subspecies

“…As expected, ZINDO/1 gave good results when applied to the interaction of a group of 3-substituted morphinans with μ, δ and κ opioid receptors 51 , and for the inhibition of wild-type and drug-resistant HIV-1 reverse transcriptase by some thiazolidenebenzenesulfonamide derivatives 52 . The problem of obtaining good numerical values for the NSD index with ab initio and DFT calculations has not yet been solved but there are some promising results 35,53 . We need to stress that the correct choice of more primitive methods (Extended Hückel Theory) can be very helpful in interpreting experimental results [54][55][56] .…”

Quantum Chemical Study of the Relationships Between Electronic Structure and Pharmacokinetic Profile, Inhibitory Strength Toward Hepatitis C Virus Ns5b Polymerase and HCV Replicons of Indole-Based Compounds

“…Its application gave good results when applied to drug-receptor interaction studies 62 and biological activities (inhibition of wild-type and drug-resistant HTV-1 reverse transcriptase 63 , accumulation of polychlorinated molecules 76 and inhibitory activity against some effects of HIV-1 and H1N1 viruses 77 ). It is worth mentioning that, in general but not always, semiempirical methods give better QSAR results that Hartree-Fock or Density Functional ones 65,81 .…”