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Outlining migrainous through dihydroergotamine-serotonin receptor interactions using quantum biochemistry


Since the early days of migrainous research, serotonin receptors (5-HTR) have been considered as a major target of drugs, depicting the 5-HT1BR and 5-HT1DR agonists among the most marketed ones for the treatment of migraine attacks. Besides, the 5-HT1BR agonist is also involved in the mechanisms underlying many neurological dysfunctions, making it a critical target for the rational development of drugs. In this context, by taking advantage of its first crystallographic structure co-crystallized with dihydroergotamine (DHE), one of the oldest and largely used antimigraine drug, a quantum biochemistry study based on the electrostatically embedded molecular fractionation with conjugate caps (EE-MFCC) scheme within the density functional theory (DFT) formalism is performed to unveil this complex's detailed binding energy. In the EE-MFCC model, each fragment is embedded surrounding the electrostatic effect of the full protein, in such a way that all atoms are replaced by their corresponding atomic charges, excluding the reference residues. Our results reveal not only the pivotal role played by the amino-acid residue D129 in the 5-HT1BR dihydroergotamine total binding energy, but also the importance of the residues D352, D123, E198, D204, F330, L126, F351, I130, V201, V200, T355 and R114 in this complex. The total binding energy reaches convergence after a pocket radius r=7.0Å, with a value around -230.93 kcal mol-1. Furthermore, we predict the relevance (energetically) of the DHE regions, as well as the influence of each protein segment to DHE-serotonin receptor binding. Finally, for completeness, we compared our results obtaining by using the EE-MFCC approach with those considering the ordinary MFCC scheme. We believe that our work is a first step using in silico quantum biochemical design as a means to influence the discovery of new drugs to treat migraine and other diseases related to the 5-HT1BR agonist.

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Publication details

The article was received on 22 Sep 2017, accepted on 27 Dec 2017 and first published on 03 Jan 2018

Article type: Paper
DOI: 10.1039/C7NJ03645K
Citation: New J. Chem., 2018, Accepted Manuscript
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    Outlining migrainous through dihydroergotamine-serotonin receptor interactions using quantum biochemistry

    J. X. Lima Neto, V. P. Soares-Rachetti, E. L. Albuquerque, V. Manzoni and U. L. Fulco, New J. Chem., 2018, Accepted Manuscript , DOI: 10.1039/C7NJ03645K

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