Rather than targeting Omicron receptor binding, in this work we focused on computationally designing new ligands targeting the internal top-tobottom cavity surrounded by the trimer central α-helices using one recent evolutionary docking method. This work continued our previous efforts to propose possible blocking of the fusion-dependent α-helix internal changes that precede viral/host membrane fusion . Such inner-cavity has been implicated in the Omicron early prefusion-fusion switch triggered after human ACE receptor recognition . This inner-cavity seems to be highly conserved in Omicron variants, since only three Omicron new mutations (Q954H, N969K, L981F) have been described that could directly affect the prefusion-fusion switch . For this, we started from previous computationally-identified star-shaped triazine-core molecules cross docking the inner-cavity of the SARS-COV-2 wild-type all-down prefusion state isolate of 2021 . The predicted targeted site of star-shaped molecules were located at the upper S2 trimer which formed a central top-tobottom cavity of 7-20 Å of diameter surrounded by 3 α-helices (Figure ). Cross binding of the inner-cavity could stabilize the α-helices at their closed prefusion state delaying or inhibiting the early switch to fusion, therefore reducing or blocking subsequent viral infection. Similar effects had been described before by experimental mutations at the 986 KV residues of the bended elbow of the S2 trimeric spikes . Therefore our previous and present objective focused on the computational exploration of possible new star-shaped compounds which may block the Omicron early fusion with drugs rather than with mutations.