Molecular Docking, ADME, toxicity, and flexibility analysis of compounds in Withania somnifera L. for dopamine D2 receptor inhibition

Öz

Withania somnifera L., often referred to as Ashwagandha or Indian ginseng, is a therapeutic herb originating from the Indian subcontinent, where it has been utilized in conventional medicine and Ayurvedic for more than 3,000 years. The dopamine D2 receptor (D2R) is essential for nervous system function, and abnormalities in its activity is linked to conditions like Parkinson's disease, schizophrenia, and substance addiction. However, many drugs targeting D2R can cause severe, sometimes life-threatening side effects because of their non-selective binding to related receptors. The purpose of this study is to examine the inhibitory effects of withaferin A, withanolide A, B, C, D, E, F, withanone, and sitoindoside IX found in W. somnifera on the D2R using molecular docking techniques. The crystal structure of the D2R (PDB: 6CM4) and the structures of the chemical compounds were procured from the RCSB Protein Data Bank and PubChem database, respectively. The preparation of the target protein and ligands was carried out using UCSF Chimera 1.17.3. Docking simulations were conducted between the D2R and risperidone, an atypical antipsychotic drug used as the reference inhibitor, along with nine compounds from W. somnifera. The Autodock Vina plugin within UCSF Chimera 1.17.3 was used for the docking process with default settings. The results were analyzed using BIOVIA Discovery Studio. Flexibility analysis of protein-ligand complexes obtained from molecular docking was performed using CABS-Flex 2.0.The ProTox 3.0 web server was used to predict the potential toxicological profiles of the compounds. As a result, the binding energies of all compounds were found to be below -5 kcal/mol. SwissADME analysis confirmed that all of these compounds adhere to Lipinski's Rule of 5 except sitoindoside IX. The findings from this research are anticipated to provide important guidance for future drug development targeting dopamine D2 receptors.

Anahtar Kelimeler

• Withania somnifera
• dopamine D2 receptor (D2R)
• molecular docking

Dopamin D2 reseptör inhibisyonu için Withania somnifera L.'daki bileşenlerin moleküler yerleştirme, ADME, toksisite ve esneklik analizi

Öz

Genellikle Ashwagandha veya Hint ginsengi olarak anılan Withania somnifera L., 3.000 yıldan uzun süredir geleneksel tıpta ve Ayurveda'da kullanılan, Hint alt kıtasından kaynaklanan bir terapötik bitkidir. Dopamin D2 reseptörü (D2R), sinir sistemi işlevi için gereklidir ve aktivitesindeki anormallikler Parkinson hastalığı, şizofreni ve madde bağımlılığı gibi durumlarla bağlantılıdır. Bununla birlikte, D2R'yi hedef alan birçok ilaç, ilgili reseptörlere seçici olmayan bağlanmaları nedeniyle bazen yaşamı tehdit eden ciddi yan etkilere neden olabilir. Bu çalışmanın amacı, W. somnifera'da bulunan withaferin A, withanolid A, B, C, D, E, F, withanone ve sitoindoside IX’un D2R üzerindeki inhibe edici etkilerini moleküler yerleştirme tekniklerini kullanarak incelemektir. D2R'nin (PDB: 6CM4) kristal yapısı ve kimyasal bileşiklerin yapıları sırasıyla RCSB Protein Veri Bankası ve PubChem veri tabanından elde edildi. Hedef protein ve ligandların hazırlanması UCSF Chimera 1.17.3 kullanılarak gerçekleştirildi. D2R ile referans inhibitör olarak kullanılan atipik bir antipsikotik ilaç olan risperidon ve W. somnifera'dan dokuz bileşen arasında yerleştirme simülasyonları gerçekleştirildi. UCSF Chimera 1.17.3 içindeki Autodock Vina eklentisi varsayılan ayarlarla yerleştirme işlemi için kullanıldı. Yerleştirme sonuçları BIOVIA Discovery Studio Yazılımı kullanılarak analiz edildi. Moleküler yerleştirme ile elde edilen protein-ligand komplekslerinin esneklik analizi CABS-Flex 2.0 kullanılarak gerçekleştirildi. Bileşiklerin potansiyel toksikolojik profillerini tahmin etmek için ProTox 3.0 web sunucusu kullanıldı. Sonuç olarak, tüm bileşiklerin bağlanma enerjilerinin -5 kcal/mol'ün altında olduğu bulundu. SwissADME analizi, sitoindoside IX dışındaki tüm bileşiklerin Lipinski'nin 5 Kuralı'na uyduğunu doğruladı. Bu araştırmadan elde edilen bulguların, dopamin D2 reseptörlerini hedef alan gelecekteki ilaç geliştirme için önemli rehberlik sağlaması bekleniyor.

Anahtar Kelimeler

• Withania somnifera
• dopamine D2 reseptörü (D2R)
• Moleküler yerleştirme

Kaynakça

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