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SARS-CoV-2 pandemic first emerged in late 2019 in China. It has since infected more than 298 million individuals and caused over 5 million deaths globally. The identification of essential proteins in a protein–protein interaction network (PPIN) is not only crucial in understanding the process of cellular life but also useful in drug discovery. There are many centrality measures to detect influential nodes in complex networks. Since SARS-CoV-2 and (H1N1) influenza PPINs pose 553 common human proteins. Analyzing influential proteins and comparing these networks together can be an effective step in helping biologists for drug-target prediction. We used 21 centrality measures on SARS-CoV-2 and (H1N1) influenza PPINs to identify essential proteins. We applied principal component analysis and unsupervised machine learning methods to reveal the most informative measures. Appealingly, some measures had a high level of contribution in comparison to others in both PPINs, namely Decay, Residual closeness, Markov, Degree, closeness (Latora), Barycenter, Closeness (Freeman), and Lin centralities. We also investigated some graph theory-based properties like the power law, exponential distribution, and robustness. Both PPINs tended to properties of scale-free networks that expose their nature of heterogeneity. Dimensionality reduction and unsupervised learning methods were so effective to uncover appropriate centrality measures. [ABSTRACT FROM AUTHOR]