DIPEPTIDYL-PEPTIDASE-4 INHIBITORS FROM TINOSPORA CRISPA AS REVEALED BY METABOLOMICS STUDY, MOLECULAR DOCKING AND MOLECULAR DYNAMICS SIMULATION APPROACHES

Öz

Objective: This study aims to identify potential compounds as inhibitors of DPP-4 from Tinospora crispa. Material and Method: Tinospora crispa stem powder was extracted by ultrasonication. The DPP-4 inhibition test used the MAK 203 screening kit protocol. LC-MS/MS was used to determine the chemical profile. MetaboAnalyst5 and SIMCA were used to analyze the dataset. Molecular docking was performed using Molegro virtual docker, and molecular dynamics simulations were performed using YASARA dynamics employing the AMBER14 force field. Result and Discussion: The percentage inhibition of DPP-4 results showed that the most active was 96% ethanol extract. Orthogonal projection to latent structure (OPLS) analysis provides that 6'-O-LactoylBorapetoside B correlates most with DPP-4 inhibitory activity based on VIP value and Y coefficient. In the docking molecular analysis, 6’-O-LactoylBorapetoside B was predicted to be active as DPP-4 inhibitors with a lower rerank score (−106.51 Kcal/Mol) than alogliptin as a reference (−96.02 Kcal/mol). In molecular dynamics simulation for 100 ns, 6’-O-LactoylBorapetoside B complex of binding with DPP-4 protein was stable with the movement of the RMSD value below 3Å. 6'-O-Lactoyl Borapetoside B has a potential of being a DPP-4-inhibitor. But these results must be tested in vitro and in vivo in order to confirm its activity as a DPP-4 inhibitor.

Anahtar Kelimeler

• 6’-O-LactoylBorapetoside B
• computer-assisted drug discovery
• DPP-4
• Tinospora crispa

Teşekkür

The author would like to thank Prof. Dr. Siswandono, Apt, Department of Pharmaceuticals Chemistry, Airlangga University, for permission and support in software facilities Molegro virtual docker.

METABOLOMİ ÇALIŞMALARI, MOLEKÜLER DOKUNMA VE MOLEKÜLER DİNAMİK SİMÜLASYON YAKLAŞIMLARIYLA ORTAYA ÇIKAN TİNOSPORA CRİSPA'DAN DİPEPTİDİL-PEPTİDAZ-4 İNHİBİTÖRLERİ

Öz

Amaç: Bu çalışmanın amacı, Tinospora Crispa'dan DPP 4'ün inhibitörleri olarak potansiyel bileşikleri tanımlamaktır. Gereç ve Yöntem: Tinospora crispa sapının tozu ultrasonikasyonla ekstrakte edildi. DPP-4 inhibisyon testinde MAK 203 tarama kiti protokolü kullanıldı. Kimyasal profilin belirlenmesinde LC-MS/MS kullanıldı. Veri setinin analizinde MetaboAnalyst5 ve SIMCA kullanıldı. AMBER14 kuvvet alanını kullanan YASARA dinamikleri kullanılarak moleküler dinamik simülasyonları yapıldı. Sonuç ve Tartışma: DPP-4'ün yüzde inhibisyonu sonuçları en aktif olanın %96 etanol ekstraktı olduğunu gösterdi. Latent yapıya dik projeksiyon (OPLS) analizi, 6'-O-LactoylBorapetoside B'nin, VIP değeri ve Y katsayısına dayalı olarak DPP-4 inhibitör aktivitesi ile en fazla korele olduğunu sağlar. Yerleştirme moleküler analizinde, 6'-O-LactoylBorapetoside B'nin, referans olarak alogliptin'den (−96.02 Kcal/mol) daha düşük bir yeniden sıralama skoru (−106.51 Kcal/Mol) ile DPP-4 inhibitörleri olarak aktif olduğu tahmin edildi. 100 ns'lik moleküler dinamik simülasyonunda, 6'-O-LactoylBorapetoside B kompleksinin DPP-4 proteini ile bağlanma kompleksi, RMSD değerinin 3Å'un altındaki hareketi ile stabildi. 6'-O-Lactoyl Borapetoside B, bir DPP-4 inhibitörü olma potansiyeline sahiptir. Ancak bu sonuçların, bir DPP-4 inhibitörü olarak aktivitesini doğrulamak için in vitro ve in vivo olarak test edilmesi gerekir.

Anahtar Kelimeler

• 6
• bilgisayar destekli ilaç keşf
• DPP-4
• Tinospora crispa

Kaynakça

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