The use of LeuT as a receptor model for antidepressant development

Lina Rustanti

Abstract


Selective serotonin re-uptake inhibitors (SSRIs) merupakan golongan antidepresan yang cukup selektif terhadap serotonin re-uptake transporter (SERT). Sertraline dan fluoxetine merupakan golongan SSRI yang mempunyai afinitas kuat terhadap SERT serta mampu menghambat neurotransmitter recycling. Akan tetapi, kedua obat tersebut juga mempunyai afinitas terhadap norepinephrine and dopamine transporter (NAT dan DAT) yang menyebabkan terjadinya efek samping. Oleh karena itu, penelitian mengenai interaksi antara SSRI dan SERT sangat penting untuk mengetahui faktor penentu interaksi obat-reseptor. Penggunaan Leucine Transporter (LeuT), model SERT yang berasal dari bakteri Aquifexaeolicus, bisa menjelaskan interaksi SSRI-SERT. Akan tetapi, karena perbedaan spesiesasal reseptor, obat yang efektif pada LeuT belum tentu efektif pada SERT. Penggunaan LeuT bisa menjelaskan interaksi SSRIs-SERT secara molekuler. Halogen binding pocket (HBP) merupakan faktor penentu dalam interaksi SSRI-SERT. LeuT memiliki~25% sekuen yang sama dengan SERT pada manusia. Konservasi pada sekuen ini ditemukan pada sisi aktif reseptordimana HPB berada. LeuT sebagai reseptor model mampu menggambarkan interaksi antara obat dan reseptor. Hasil penemuan tersebut sangat bermanfaat untuk pengembangan obat antidepresan yang lebih selektif. (Health Science Indones 2010; 1: 51 - 57)

Kata kunci: LeuT, antidepresan, serotonin re-uptake transporter

Abstract

Selective serotonin re-uptake inhibitors (SSRIs) have been considered to be promising drugs in psychiatric practice because of their selectivity to serotonin re-uptake transporter (SERT). Sertraline and fluoxetine are considered to be effective SSRIs as their ability in binding SERT and inhibit neurotransmitter recycling. However, they also bind norepinephrine and dopamine transporter (NAT and DAT) that cause undesirable effects. Thus, the study of drug-receptor interaction between SSRIs and SERT is important to gauge the active site of the drugs. By using Leucine Transporter (LeuT) from Aquifexaeolicusas a SERT model, the mode of SSRIs-SERT interaction was revealed. Nonetheless, it is uncertain whether the drugs that bind to LeuT would be effective to human SERT because of the high evolutionary convergence between them. Halogenbinding pocket (HBP) was found to be the key determinant in the drug-receptor interaction. LeuT has ~25% sequence similarity to human SERT with highly conserved amino acid sequences in the active site of these receptors, in which HBP is located. LeuT as the receptor model revealed the interaction between drugs and receptors. All these findings are very useful to develop more selective antidepressant medicines. (Health Science Indones 2010; 1: 51 - 57)

Keywords


LeuT, antidepressant, serotonin re-uptake transporter

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Health Science Journal of Indonesia

ISSN: 2087-7021
EISSN: 2338-3437