Molecular modelling analysis of the activity of opioids
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Date
2013-07-04
Authors
Tennakoon, T. M. S. P.
Wickramaratne, D. B. M.
Weerasooriya, R.
Journal Title
Journal ISSN
Volume Title
Publisher
The University of Peradeniya
Abstract
Opioids are used as analgesics to relieve pain. Their molecular structures are derived mainly from morphine but some new synthetic and semisynthetic agents have novel structures. The potency/strength of these opioids vary with a large range even though they have similar pharmacophore atoms. Some opioids such as morphine need 10mg to exert a certain level of bioactivity whereas fentanyl exerts the same effect with only 0.1mg.This study aimed to determine the molecular root cause for the variations of the potency of opioids. The outcome can be used to provide hints for future computer aided drug designing.
Seventeen opioids were modeled in HyperChem Professional 8.5 version software package. They were first geometrically optimized using Molecular Mechanics (MM+) force field and further enhanced by using a Semi empirical modeling method. Then computations were performed according to the guidelines of HyperChem 8.5 manual. The results were compared against the relative potency of the opioids.
Relative potency of the opioids increased with the increase of the degree of overlapping of Highest Occupied Molecular Orbitals (HOMOs) with electronegative regions of the molecule. Also, the opioids with overlapping HOMOs with the pharmacophore atoms and carbon atoms outside the pharmacophore and relatively lesser HOMO and LUMO energy differences had higher relative potencies.
The incidence of increased relative potency with the overlapping of HOMOs with the electronegative areas and the pharmacophore atoms indicate that the increase of electron donor ability of the drug molecule has enabled it to bind/interact with the receptor atoms more efficiently. Inverse correlation between potency and HOMO-LUMO energy difference shows that increased reactivity has increased potency of the drugs.
According to the findings of this study, the efficacy and the potency of opioids were increased with electron donating properties at electronegative areas of the drug molecule and by increasing the number of pharmacophore atoms covered by the HOMOs.
Description
Keywords
Analgesics , Opioids , Molecular modelling
Citation
Peradeniya University Research Sessions PURSE - 2012, Book of Abstracts, University of Peradeniya, Sri Lanka, Vol. 17, July. 4. 2012 pp. 275