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Artificial Intelligence in Health EBNA1 inhibitors against EBV in NPC

While high-throughput screening can identify active Nasopharyngeal carcinoma (NPC) is strongly
compounds at low concentrations, it often produces a low associated with Epstein-Barr virus (EBV). NPC typically
hit rate or high false positives. This leads to a significant affects individuals in their mid-40s and is more prevalent
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discrepancy between the number of hits identified and the in men. It consistently exhibits EBV positivity, regardless
number of viable lead compounds, which leads to wastage. of geographic location. Annually, NPC accounts for

One way to negate this problem is using quantitative approximately 90,000 cases and 50,000 deaths recorded
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structure-activity relationship (QSAR) in drug discovery. globally. Its distribution is unique, with Asian countries
QSAR is a ligand-based drug design method that uses representing around 80% of documented cases and
mathematical models to correlate the chemical features of mortality rates. In Malaysia, NPC ranks as the fourth
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inhibitors to their bioactivity. QSAR models streamline most common cancer among males. Among the Bidayuh
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drug discovery by predicting compound activity based community, part of Malaysia’s indigenous population, the
on their structure and properties, allowing researchers to risk of NPC is notably elevated, with men and women
prioritize promising candidates. This targeted approach experiencing a 2.3-fold and 1.9-fold increase, respectively,
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reduces the need for extensive testing, saving time, compared to other populations during the same period.
resources, and materials while accelerating the research NPC poses a significant health concern, among which EBV
process. It optimizes resource allocation and promotes latent infection stands out as a prominent contributor.
sustainable research practices by focusing efforts on EBV is a virus capable of infecting epithelial and B cells,
compounds with a higher likelihood of success. Another facilitating its persistence within the host and transmission
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advantage is that QSAR aids in designing active molecules among humans. A critical protein in maintaining viral
in a “greener” way by reducing the need for extensive stability and promoting viral gene expression is called
experimental synthesis and testing on animals. A study the EBV nuclear antigen 1 (EBNA1). EBNA1 interacts
examined the toxicity of various ionic liquids (ILs), which with the oriP region of the EBV genome, forming dimers
have the potential to harm aquatic life. Their study utilized and complexes crucial for DNA looping and maintaining
advanced QSAR techniques to develop reliable models for genome stability. 18,19 In addition, EBNA1 recruits cellular
predicting IL toxicity without animal testing. Their QSAR proteins to facilitate DNA replication. EBNA1 binds to
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models demonstrated high predictive accuracy, with the Family of Repeats (FR) element during cell division,
classification models achieving over 86% accuracy and
regression models showing a correlation (R ) >0.90 in the tethering EBV episomes to cellular chromosomes for proper
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test data. These high-performance models provided strong segregation. EBNA1 also activates EBV gene transcription
by interacting with the FR element, with specific regions
predictions and pinpointed the structural elements of ILs 24
contributing to their cytotoxicity. These QSAR models within EBNA1 being crucial for this function. Moreover,
offer valuable tools for designing safer and environmentally EBNA1 affects several cellular signaling pathways in cell
friendly ILs. Notably, QSAR-based virtual screening has transformation and growth. It amplifies STAT1 signaling,
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emerged as a pivotal approach in contemporary scientific enhances interferon responsiveness, and inhibits the
investigations, facilitating the identification of potential transforming growth factor beta and nuclear factor kappa
drug candidates. QSAR has been used to design chalcone B pathways, ultimately promoting viral persistence and
derivatives that outperform standard tuberculosis drugs, oncogenesis. 25,26 EBNA1 also disrupts promyelocytic
identify potent neuraminidase inhibitors for influenza A, nuclear bodies, impairing DNA repair, p53 activation, and
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identify potent inhibitors for 5-HT receptors for mood apoptosis in response to DNA damage. This disruption is
1A
and anxiety disorders, and identify potential antimalarial mediated by interactions with cellular proteins ubiquitin-
activity in compounds that have low toxicity towards specific-processing protease 7 (USP7) and casein kinase 2,
the mammalian cell. 7-10 QSAR was also used to identify leading to promyelocytic leukemia protein degradation. 27-29
critical structural features enhancing the inhibitory effects EBNA1 interacts with USP7, stabilizing its binding and
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of compounds against liver carcinoma cells in tumor- preventing p53 stabilization protease. Consequently,
targeting drug studies. In antipsychotic/antidepressant cells expressing EBNA1 exhibit reduced p53 accumulation
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studies, QSAR models have aided in predicting the upon DNA damage, facilitating cell survival and potentially
activities of natural compounds against specific receptors, contributing to tumorigenesis. EBNA1 expression also
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offering potential alternatives to synthetic drugs. QSAR correlates with increased oxidative stress, characterized
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methodologies were also used to clarify physicochemical by elevated reactive oxygen species (ROS) levels and DNA
factors influencing the activity and cytotoxicity of damage. This phenomenon, mediated by the upregulation of
compounds against human immunodeficiency viruses and ROS-generating enzyme NADPH oxidase 2 (NOX2), may
influenza viruses in antiviral drug studies. 13,14 promote genomic instability and tumor development. 31,32

Volume 2 Issue 1 (2025) 94 doi: 10.36922/aih.4375