Nuwarda, Rina Fajri
(2015)
Potential Neuraminidase Inhibitors Via Virtual Screening, Kinetic Studies, And Adme Predictions.
Masters thesis, Universiti Sains Malaysia.
Abstract
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.
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