Molecular Dynamics and MM-PBSA Studies for Deciphering Molecular Interactions of Valproic Acid with CYP2C9 Mutants F114L and I207T

Year 2021, Volume: 25 Issue: 1, 64 - 73, 20.04.2021

Ahmet Can Timuçin

https://doi.org/10.19113/sdufenbed.801973

Abstract

Valproic Acid (VPA) is a widely used drug, particularly in neuropsychiatric disorders, while showing promise in other types of diseases such as cancer. VPA metabolism via cytochrome P450 (CYP) pathway is responsible from only ~10% of the total drug dose. However, due to high risk of severe adverse reactions in liver and pancreas, interaction of VPA with CYP2C9 remains to be delineated chiefly in CYP2C9 mutants. Hence, here we implemented a molecular dynamics study, followed by MM-PBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) method based relative binding energy estimation to understand how F114L and I207T CYP2C9 mutants changed their binding mode towards VPA in comparison to wild type (WT) CYP2C9. Results indicated that while F114L and I207T mutants have showed significant decrease in total relative binding energy, compared with WT, there were a clear shift of occupied amino acids responsible for VPA interaction in mutants vs WT. Overall, here for the first time in literature, this novel shift of VPA interacting amino acids in F114L and I207T mutants were reported. Limitations and future perspective of the data were also discussed.

Keywords

CYP2C9, MD Simulations, MM-PBSA, Valproic Acid

Thanks

Molecular dynamics and MM-PBSA calculations described in this study were fully implemented at TUBITAK ULAKBIM, High Performance and Grid Computing Center (TRUBA resources).

Valproik Asit ile CYP2C9 Mutantları F114L ve I207T Moleküler Etkileşimlerinin Çözümlenmesi için Moleküler Dinamik ve MM-PBSA Çalışmaları

Abstract

Valproik asit (VPA), özellikle nöropsikiyatrik bozukluklarda kullanılan bir ilaç olup, kanser gibi diğer tip hastalıklarda da umut vaat etmektedir. Sitokrom P450 (CYP) yolağı tarafından gerçekleştirilen VPA metabolizması toplam ilaç dozunun sadece %10 kadarıdır. Ancak, karaciğer ve pankreasta şiddetli yan etki reaksiyonları gösterme riski yüksek olduğu için, VPA`nın CYP2C9 ile ve özellikle CYP2C9 mutantları ile nasıl etkileştiği açıklanmayı beklemektedir. Bu nedenle, biz burada moleküler dinamik çalışmaları ve devamında yapılan MM-PBSA (Moleküler Mekanik Poisson-Boltzmann Yüzey Alanı) metodu tabanlı bağıl bağlanma enerjisi tahmini ile CYP2C9 mutantları F114L ve I207T`nin VPA ile bağlanma modunun doğal fenotipli (WT) CYP2C9`a göre nasıl değiştiğini anlamayı amaçladık. Sonuçlar, F114L ve I207T mutantlarının toplam bağıl bağlanma enerjilerinin doğal fenotipe göre önemli miktarda düştüğünü göstermiş olup, ayrıca mutantların VPA etkileşimi için kullandıkları amino asitlerde de, doğal fenotipe göre net bir değişim olduğunu ortaya koymuştur. Tümde, literatürde bir ilk olarak, VPA ile etkileşen amino asitlerdeki bu özgün değişim raporlanmıştır. Verilerin kısıtlamaları ve gelecek perspektifi de ayrıca tartışılmıştır.

Keywords

CYP2C9, MD Simulasyonları, MM-PBSA, Valproik Asit

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