Naslov
The effect of deuteration on the histamine binding profile towards H2 receptor: A computational insight into the modified hydrogen bonding interactions

Autori
Hok, Lucija ; Mavri, Janez ; Vianello, Robert

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, neobjavljeni rad, znanstveni

Skup
Brainhack Zagreb 2020

Mjesto i datum
Online, 12.11.2020

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Nije recenziran

Ključne riječi
deuteration ; heavy drugs ; histamine receptor ; hydrogen bonding ; receptor activation

Sažetak
Histamine is an important mediator and neurotransmitter that is involved in a broad spectrum of central and peripheral physiological as well as pathophysiological processes. It exerts its specific effects by the activation of four receptor subtypes (H1– H4), which belong to the family of G-protein coupled receptors. Replacing a lighter hydrogen atom with deuterium has been recently recognized as a powerful tool in the field of the medicinal chemistry not only to examine the mechanism of action of the investigated substances, but also to improve pharmaceutical profiles of the already marketed drugs. In this work, we used a range of computational techniques to get a deeper insight into the histamine binding to the H2 receptor binding site, and whether this process is modulated upon the non-selective deuteration, which would confirm the assumption that ligand binding is governed by hydrogen bonding interactions. Molecular docking identified the area between third and fifth transmembrane α-helices as the likely binding pocket and the subsequent molecular dynamics simulation identified Asp98 as the most dominant residue, accounting for 40% of the total binding energy, established through a persistent hydrogen bonding with the histamine positive amino group. Lastly, quantum-chemical calculations supported the deuteration-induced affinity increase, with the calculated difference in the binding free energy of –0.85 kcal/mol, being in excellent agreement with an experimental value of –0.76 kcal/mol, thus confirming the relevance of hydrogen bonding for the H2 receptor activation.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Farmacija

POVEZANOST RADA