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Pregled bibliografske jedinice broj: 1195712

A computational insight into the effect of deuteration on the H2 receptor histamine binding profile


Hok, Lucija; Mavri, Janez; Vianello, Robert
A computational insight into the effect of deuteration on the H2 receptor histamine binding profile // Virtual Winter School on Computational Chemistry, SFPs
Online, 2022. (poster, međunarodna recenzija, neobjavljeni rad, znanstveni)


CROSBI ID: 1195712 Za ispravke kontaktirajte CROSBI podršku putem web obrasca

Naslov
A computational insight into the effect of deuteration on the H2 receptor histamine binding profile

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

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

Izvornik
Virtual Winter School on Computational Chemistry, SFPs / - , 2022

Skup
Virtual Winter School on Computational Chemistry 2022

Mjesto i datum
Online, 21.02.2022. - 25.02.2022

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

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

Sažetak
In the past few years, deuteration has become one of the most promising tools in medicinal chemistry to overcome problems in terms of metabolism- mediated toxicity, low bioactivation, and drug interactions. Furthermore, precise deuteration goes beyond the pure and simple amelioration of the pharmacokinetic properties, providing an opportunity to decrease the degree of racemisation, reduce the dose of coadministered boosters, and contribute to the investigation of mechanisms of action for various endo- and xenobiotics [1]. In this work, we used a range of computational techniques to reveal an increased histamine affinity for its H2 receptor upon nonselective deuteration, which was interpreted through altered hydrogen bonds within the receptor and the aqueous solution preceding the binding [2]. Molecular docking procedure identified the area between third and fifth transmembrane α-helices as the likely binding site. The subsequent molecular dynamics simulation recognized Asp98 as the most dominant residue, whose persistent hydrogen bond with the histamine −NH3+ group accounts for the 40% of the total binding energy, and is further stabilised through interaction with Tyr250 (Figure 1). Lastly, quantum-chemical calculations supported the deuteration-induced affinity increase by calculating the difference in the binding free energy of −0.85 kcal mol−1, which is in excellent agreement with an experimental value of −0.75 kcal mol−1. All these calculations confirm the initial hypothesis that hydrogen bonds are crucial in the H2 receptor activation and underline precise deuteration as a useful tool to improve drug efficiency. [1] T. Pirali, M. Serafini, S. Cargnin, A. A. Genazzani, J. Med. Chem. 62 (2019) 5276−5297. [2] L. Hok, J. Mavri, R. Vianello, Molecules 25 (2020) 6017.

Izvorni jezik
Engleski

Znanstvena područja
Kemija



POVEZANOST RADA


Projekti:
EK-KK.01.1.1.04.0013 - Inovativna rješenja u katalitičkim proizvodnim procesima za potrebe farmaceutske industrije (CAT PHARMA) (Kirin, Srećko, EK ) ( CroRIS)

Ustanove:
Institut "Ruđer Bošković", Zagreb

Profili:

Avatar Url Robert Vianello (autor)

Avatar Url Lucija Hok (autor)

Poveznice na cjeloviti tekst rada:

Pristup cjelovitom tekstu rada winterschool.cc

Citiraj ovu publikaciju:

Hok, Lucija; Mavri, Janez; Vianello, Robert
A computational insight into the effect of deuteration on the H2 receptor histamine binding profile // Virtual Winter School on Computational Chemistry, SFPs
Online, 2022. (poster, međunarodna recenzija, neobjavljeni rad, znanstveni)
Hok, L., Mavri, J. & Vianello, R. (2022) A computational insight into the effect of deuteration on the H2 receptor histamine binding profile. U: Virtual Winter School on Computational Chemistry, SFPs.
@article{article, author = {Hok, Lucija and Mavri, Janez and Vianello, Robert}, year = {2022}, keywords = {deuteration, heavy drugs, histamine receptor, hydrogen bonding, receptor activation}, title = {A computational insight into the effect of deuteration on the H2 receptor histamine binding profile}, keyword = {deuteration, heavy drugs, histamine receptor, hydrogen bonding, receptor activation}, publisherplace = {Online} }
@article{article, author = {Hok, Lucija and Mavri, Janez and Vianello, Robert}, year = {2022}, keywords = {deuteration, heavy drugs, histamine receptor, hydrogen bonding, receptor activation}, title = {A computational insight into the effect of deuteration on the H2 receptor histamine binding profile}, keyword = {deuteration, heavy drugs, histamine receptor, hydrogen bonding, receptor activation}, publisherplace = {Online} }




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