Molecular Docking Study of Midostaurin, an Effective Drug in the Treatment of Myeloid Leukemia

Year 2023, , 2 - 10, 30.06.2023

Sefa Çelik , Gözde Yılmaz , Ayşen Özel , Sevim Akyüz

https://doi.org/10.56171/ojn.1102513

Abstract

Midostaurin (C35H30N4O4) is a multi-target kinase inhibitor used to treat some types of acute myeloid leukemia in combination with other chemotherapy agents. Firstly, the structural preferences of the Midostaurin were evaluated due to the importance to determine the most stable conformer of a bioactive molecule to elucidate its bioactivity. The conformational analysis of the Midostaurin molecule was performed using the PM3, a semi-experimental method. The three most stable conformers and their relative energies were determined. The Epidermal Growth Factor receptor (EGFR) is an integral membrane protein, and its over-expression is associated with the development of a wide variety of tumors. For this reason, EGFR inhibitors can act as anticancer drugs as preventing the growth of EGFR-expressing tumors and increasing the survival rates of patients. On the other hand, DNA is an important target for anticancer drugs. To elucidate the anticancer properties of Midostaurin, the molecular docking simulations were performed against EGFR and DNA targets. The binding modes and binding affinities of the ligand-target receptor complexes were determined. Midostaurin showed strong binding affinity to DNA (G = -8.6 kcal/mol) and EGFR (G = - 9.6 kcal/mol). The results revealed the significant anti-tumor effect of Midostaurin.

Keywords

Conformational analysis, DNA, EGFR, Midostaurin, molecular docking

Supporting Institution

Research funds of Istanbul University

Project Number

ÖNAP-2423

Miyeloid Lösemi Tedavisinde Etkili Bir İlaç Olan Midostaurinin Moleküler Kenetlenme Çalışması

Abstract

Midostaurin (C35H30N4O4), diğer kemoterapi ajanları ile birlikte bazı akut miyeloid lösemi tiplerini tedavi etmek için kullanılan multi-target kinaz inhibitörüdür. Biyoaktif bir molekülün biyoaktivitesini gösterdiği en kararlı konformerinin belirlenmesinin önemi dolayısıyla ilk olarak Midostaurin’in yapısal tercihleri bulunup değerlendirilmiştir. Midostaurin molekülünün konformasyonel analizi, yarı deneysel bir metot olan PM3 kullanılarak yapılmıştır. En kararlı üç konformer ve bunların bağıl enerjileri belirlenmiştir. Bütünleyici bir zar proteini olan Epitermal Büyüme faktörü reseptörü (EGFR) ve aşırı ekspresyonu, çok çeşitli tümörlerin gelişimi ile ilişkilidir. Bu nedenle, EGFR inhibitörleri, EGFR eksprese eden tümörlerin büyümesini önleyerek ve hastaların hayatta kalma oranlarını artırarak antikanser ilaçlar olarak işlev görebilir. Ek olarak, DNA antikanser ilaçlar için önemli bir hedeftir. Midostaurin’in antikanser özelliklerini aydınlatmak için EGFR ve DNA’ya karşı moleküler kenetlenme simülasyonları yapılmıştır. Ligand-hedef reseptör komplekslerinin bağlanma modları ve bağlanma afiniteleri belirlenmiştir. Midostaurin, DNA (ΔG = -8.6 kcal/mol) ve EGFR (ΔG = - 9.6 kcal/mol) ile güçlü bağlanma afinitesi göstermiştir. Sonuçlar, Midostaurin'in önemli anti-tümör etkisini ortaya çıkarmıştır.

Keywords

Konformasyon analizi, DNA, EGFR, Midostaurin, moleküler kenetlenme

Project Number

ÖNAP-2423

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