Potential Neuraminidase Inhibitors Via Virtual Screening, Kinetic Studies, And Adme Predictions

• Main Author: Nuwarda, Rina Fajri
• Format: Thesis
• Language: English
• Published: 2015
• Subjects: RS1-441 Pharmacy and materia medica
• Online Access: http://eprints.usm.my/31990/1/RINA_FAJRI_NUWARDA_24%28NN%29.pdf; http://eprints.usm.my/31990/
• Institution: Universiti Sains Malaysia

Aktiviti neuraminidase (NA) memainkan peranan yang penting dalam jangkitan oleh virus influenza dengan memudahkan pelepasan virion yang baru ditubuhkan daripada reseptor sel tuan rumah dan menggalakkan jangkitan kepada selsel atau organ-organ lain. Disebabkan kemunculan rintangan virus terhadap perencat NA sedia ada, penemuan perencat NA baru amat diperlukan. Dalam kajian ini, pemeriksaan maya berdasarkan pendokan sebatian-sebatian daripada pangkalan data NCI untuk memilih dengan pantas hit in silico bagi menjadi potensi perencat NA telah dijalankan. Satu kaedah in vitro baru telah dicuba untuk membangunkan perencatan asai NA dengan menggunakan teknologi AlphaScreenTM dengan Alpha-1-Asid Glikoprotein sebagai substrat. Malangnya, usaha ini tidak berjaya mungkin disebabkan pemisahan tidak spesifik asid sialik oleh NA. Selepas itu, asai MUNANA tradisional telah dijalankan untuk menyiasat aktiviti perencatan dan parameter kinetik sebatian perencat. Akhir sekali, sebatian-sebatian terpilih dikaji untuk ciri farmakokinetik in silico mereka. Dari pangkalan data NCI, 1541 sebatian telah berjaya disaring untuk mendapatkan 40 kompaun hit in silico diikuti oleh asai MUNANA untuk menentukan IC50 mereka. Neuraminidase (NA) activity plays an important role in the infection by influenza viruses by facilitating the release of the newly formed virions from the host cell receptor and promotes its infection to other cells or organs. With the emergence of viral resistance towards the existing NA inhibitors, the discovery of new NA inhibitors is urgently needed. In this work, docking-based virtual screening of large compounds from NCI database to rapidly select in silico hits to be potential NA inhibitors was carried out. A new in vitro method has been attempted to be developed for NA inhibition assay by utilizing AlphaScreenTM technology with Alpha-1-Acid glycoprotein as a substrate. Unfortunately, this effort was unsuccessful probably due to the non-specific cleavage of sialic acid by NA. Subsequently, a traditional MUNANA assay was performed to investigate the inhibitory activities and kinetic parameters of the inhibitor compounds. Finally, the selected compounds were studied for their pharmacokinetic properties in silico. From the NCI database, 1541 compounds have been successfully screened and 40 in silico hits compounds were obtained, and assayed to determine their IC50s.