Two years have passed since the beginning of the SARS-CoV-2 pandemic and the continual emergence of SARS-CoV-2 mutated viral strains has led to continual re-evaluation of the current therapeutic options. Herein we continued an analysis of the interactions of SARS-CoV-2 Spike (S), protein with human angiotensin converting enzyme (ACE-2), and compared these interactions with those of the variants of concern (VOCs), and variants of interest (VOIs), that have emerged since August 2021 with ACE-2. We have also compared the binding affinities of several possible S-protein inhibitors with the binding affinity of these same inhibitors with the VOCs and VOIs by means of in silico molecular docking studies. The highest binding potential inhibitor was complexed with the spike proteins and docked with ACE-2. The protein-protein binding decreases when the inhibitor is bound to the S-proteins, however the binding affinity to the inhibitors varies. The inhibitors show decreased binding affinity to the VOCs mutated S-proteins and similar affinity to the VOIs in comparison to SARS-CoV-2, indicating the variability of binding amongst the variants deems the S-protein a poor target for the therapeutic approach.