MemCross: Accelerated Weight Histogram method to assess membrane permeability

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15640%2F23%3A73621757" target="_blank" >RIV/61989592:15640/23:73621757 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0005273623000020?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0005273623000020?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bbamem.2023.184120" target="_blank" >10.1016/j.bbamem.2023.184120</a>

Jazyk výsledku

angličtina

Název v původním jazyce

MemCross: Accelerated Weight Histogram method to assess membrane permeability

Popis výsledku v původním jazyce

Passive permeation events across biological membranes are determining steps in the pharmacokinetics of xe-nobiotics. To reach an accurate and rapid prediction of membrane permeation coefficients of drugs is a complex challenge, which can efficiently support drug discovery. Such predictions are indeed highly valuable as they may guide the selection of potential leads with optimum bioavailabilities prior to synthesis. Theoretical models exist to predict these coefficients. Many of them are based on molecular dynamics (MD) simulations, which allow calculation of permeation coefficients through the evaluation of both the potential of mean force (PMF) and the diffusivity profiles. However, these simulations still require intensive computational efforts, and novel meth-odologies should be developed and benchmarked. Free energy perturbation (FEP) method was recently shown to estimate PMF with a significantly reduced computational cost compared to the adaptive biasing force method. This benchmarking was achieved with small molecules, namely short-chain alcohols. Here, we show that to estimate the PMF of bulkier, drug-like xenobiotics, conformational sampling is a critical issue. To reach a suf-ficient sampling with FEP calculations requires a relatively long time-scale, which can lower the benefits related to the computational gain. In the present work, the Accelerated Weight Histogram (AWH) method was employed for the first time in all-atom membrane models. The AWH-based protocol, named MemCross, appears affordable to estimate PMF profiles of a series of drug-like xenobiotics, compared to other enhanced sampling methods. The continuous exploration of the crossing pathway by MemCross also allows modeling subdiffusion by computing fractional diffusivity profiles. The method is also versatile as its input parameters are largely insensitive to the molecule properties. It also ensures a detailed description of the molecule orientations along the permeation pathway, picturing all intermolecular interactions at an atomic resolution. Here, MemCross was applied on a series of 12 xenobiotics, including four weak acids, and a coherent structure-activity relationship was established.

Název v anglickém jazyce

MemCross: Accelerated Weight Histogram method to assess membrane permeability

Popis výsledku anglicky

Passive permeation events across biological membranes are determining steps in the pharmacokinetics of xe-nobiotics. To reach an accurate and rapid prediction of membrane permeation coefficients of drugs is a complex challenge, which can efficiently support drug discovery. Such predictions are indeed highly valuable as they may guide the selection of potential leads with optimum bioavailabilities prior to synthesis. Theoretical models exist to predict these coefficients. Many of them are based on molecular dynamics (MD) simulations, which allow calculation of permeation coefficients through the evaluation of both the potential of mean force (PMF) and the diffusivity profiles. However, these simulations still require intensive computational efforts, and novel meth-odologies should be developed and benchmarked. Free energy perturbation (FEP) method was recently shown to estimate PMF with a significantly reduced computational cost compared to the adaptive biasing force method. This benchmarking was achieved with small molecules, namely short-chain alcohols. Here, we show that to estimate the PMF of bulkier, drug-like xenobiotics, conformational sampling is a critical issue. To reach a suf-ficient sampling with FEP calculations requires a relatively long time-scale, which can lower the benefits related to the computational gain. In the present work, the Accelerated Weight Histogram (AWH) method was employed for the first time in all-atom membrane models. The AWH-based protocol, named MemCross, appears affordable to estimate PMF profiles of a series of drug-like xenobiotics, compared to other enhanced sampling methods. The continuous exploration of the crossing pathway by MemCross also allows modeling subdiffusion by computing fractional diffusivity profiles. The method is also versatile as its input parameters are largely insensitive to the molecule properties. It also ensures a detailed description of the molecule orientations along the permeation pathway, picturing all intermolecular interactions at an atomic resolution. Here, MemCross was applied on a series of 12 xenobiotics, including four weak acids, and a coherent structure-activity relationship was established.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

21002 - Nano-processes (applications on nano-scale); (biomaterials to be 2.9)

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2023

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES

ISSN

0005-2736

e-ISSN

1879-2642

Svazek periodika

1865

Číslo periodika v rámci svazku

3

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

12

Strana od-do

—

Kód UT WoS článku

000992180200001

EID výsledku v databázi Scopus

2-s2.0-85146694323