Design of A New Candidate BACE-1 Inhibitor with Computational Chemistry Method in The Treatment of Alzheimer's Disease

Abstract

In recent years, the incidence of Alzheimer's disease has increased with the increase in the elderly population all over the world. Alzheimer's disease is related to the abnormality and disorder of more than one system, its pathogenesis is complex. Therefore, there is no ideal drug currently used to prevent and treat Alzheimer's, and many studies on Alzheimer's are ongoing. In the related study, docking studies were performed with the 2WJO pdb id coded crystal structure of the BACE-1 enzyme, which is associated with Alzheimer's disease, with the Lupeol molecule and 32 newly designed Lupeol derivatives using Autodock Vina software. In this context, first of all, conformers and geometric optimizations of Lupeol and its derivatives were performed with Spartan'16 software. On the other hand, visualizations and interaction maps between protein and ligands were made by Discovery Studio Visualer software. As a result of docking studies, four molecules as L-28, L-23, L-27 and L-31 with higher binding energies than Lupeol structures are determined. In the derivatization studies, it has been determined that the design of more hydrophilic structures for the active site gives better binding energy. Experimental examination of the relevant molecules is recommended.

Keywords

• Alzheimer
• Docking
• Lupeol
• BACE-1
• AutoDock Vina

Moleküler Kenetlenme Simülasyonları ile Yeni Aday BACE-1 İnhibitörü Tasarımı

Abstract

Dünyadaki yaşlı nüfusta görülen artış Alzheimer hastalığının daha yaygın bir hale gelmesine neden olmuştur. Alzheimer hastalığı birden fazla sistemin anormalliği ve bozukluğu ile ilgilidir, patogenezi karmaşık olası sebebi ile önlemek ve tedavi etmek için şu an kullanılan ideal bir ilaç yoktur ve ilaç araştırmaları devam etmektedir. İlgili çalışmada, Alzheimer hastalığı ile ilişkili olan BACE-1 enziminin 2WJO pdb id kodlu kristal yapısı ile lupeol molekülü ve 32 adet yeni tasarlanan Lupeol türevi ile Autodock Vina yazılımı kullanılarak kenetlenme çalışmaları yapılmıştır. Bu bağlamda öncelikle, Lupeol ve türevlerinin konformerleri ve geometrik optimizasyonları Spartan’16 yazılımı ile gerçekleştirilmiştir. Discovery Studio Visualer yazılımında ise görselleştirmeler yapılarak protein ve ligantlar arasındaki etkileşim haritaları çizilmiştir. Kenetlenme çalışmaları sonucunda, Lupeol yapılarından daha yüksek bağlanma enerjilerine sahip L-28, L-23, L-27 ve L-31 olmak üzere dört molekül belirlenmiştir. Yapılan türevlendirme çalışmalarında aktif bölge için daha hidrofilik yapıların tasarımının daha iyi bağlanma enerjisi verdiği tespit edilmiştir. İlgili moleküllerin deneysel olarak incelenmesi önerilmektedir.

Keywords

• Alzheimer
• Kenetlenme
• Lupeol
• BACE-1
• AutoDock Vina

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