The search for effective and safe therapeutics and vaccines for COVID-19 is one of, if not the top most, the top priorities in today’s medicinal and pharmaceutical research. In COVID-19 drug discovery and development, computational methodologies have played a significant role, not only in accelerating and economizing the process but also providing a better mechanistic understanding of a drug candidate’s interactions with specific viral targets. One interesting drug target for the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is its spike protein, which plays a crucial role in the virus’s transmissibility and pathogenicity. The SARS-CoV-2 spike is a structural protein crowning the surface of the virus. The spikes are transmembrane glycoproteins primarily involved in the attachment to host cell receptors, initiating viral-host cell fusion and consequently facilitating viral entry. Such phenomenon is the first step in SARS-CoV-2 pathogenesis. Each coronavirus species showcases distinct domains, particularly the receptor-binding domain (RBD) located at the S1 subunit, to recognize various host cell receptors. For SARS-CoV-2, these receptors include the angiotensin-converting enzyme 2 (ACE2) and the glucose-regulated protein (GRP78). In the process of viral entry, host cell transmembrane protease serine type 2 (TMPRSS2) is employed to prime the fusion activity of the virus. Furthermore, the resulting fragments from the priming of spike may be recognized by neuropilin-1 (NRP-1), which consequently binds to the spike protein thus enhancing SARS-CoV-2 infectivity. In this chapter, we present virtually screened natural products, such as alkaloids, sterols, peptides, polyphenols, and terpenoids, which showed antagonistic potential to host cell recognition, viral attachment and fusion through binding with various receptor-binding regions of SARS-CoV-2 spike protein for ACE2, GRP78, and NRP-1 as well as host cell transmembrane TMPRSS2. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.