The SARS-CoV-2 claimed millions of lives, globally. Occurring from Wuhan (wild type) in December, 2019, it constantly mutated to Omicron (B.1.1.529), the predecessor to Delta. Omicron having ~ 32 spike mutations has variable infectivity-multiplicity-immuno-invasive properties. Understanding of its mutational effect on ACE2-binding/disease severity and developing preventive/therapeutic strategies are important. The binding affinities of Wuhan/Delta/Omicron spikes (PDB/GISAID/SWISS-MODEL) were docked (HADDOCK2.4) with ACE2 and compared by competitive-docking (PRODIGY). The protein structural stability was verified by kinetic-data/Ramachandran-plot (Zlab/UMassMedBioinfo). After several trials, a 59 amino acid (453ARG-510VAL) peptide-cut (Expasy-server) of the wild-type spike RBD with some desired mutants (THR500SER/THR500GLY/THR500ALA/THR500CYS) was blindly/competitively docked (PyMOL-V2.2.2) to block the Omicron-ACE2 binding. We examined molecular dynamic simulation (iMOD-server, with 9000 cycles/300 k-heating/1 atm pressure for system equilibration for 50 ns-run) of ACE2 and two CUTs with different SARS-CoV-2 variants. The binding-affinity of Omicron-ACE2 is slightly higher than the rest two in competitive docking setup. During individual (1:1) docking, Omicron showed little higher than wild type but much weaker binding affinity than Delta. Competitive docking suggests ten H-bonding (1.3-2.4 Å) with highly favorable energy values/Van-der-Walls-force/Haddock score for more stable-binding of Omicron-RBD with ACE2. Blind docking of different CUTs (wild/mutants) and Omicron to ACE2 completely rejected the Omicron-RBD from ACE2-target. The best blocking/binding affinity of -16.4 and -13 kcal/mole were observed in the case of THR500SER and THR500GLY, respectively, with multiple H-bonding 1.9-2.2 Å. These are supported by the MD-simulation results. So, the spike binding affinities were Delta > Omicron > wild in 1:1 docking with ACE2. Considering the wild type is non-existing nowadays, Omicron showed less ACE2 binding properties. The 59 cut of spike-RBD and its mutant THR500SER/THR500GLY may be further screened as universal blockers of this virus.The online version contains supplementary material available at 10.1007/s11224-022-02022-x.