The COVID-19 (Corona Virus Disease 19) pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is causing enormous difficulties in the worlds economies and there is uncertainty as to whether the current prophylactic measures will offer adequate protection globally after the appearance of virus variants that like that indicated as Omicron emerged in the presence of global vaccine-based immunization. While several studies are available describing the main differences in the spike protein of Omicron compared to the other variants previously emerged there was no structural insights into the 3CL-protease (3CLpro) associated to the new variant. Herein we performed a computational study based on genomic data and amino acid sequences available in the most updated COVID-19-related databases that allowed us to build up in silico the 3D structure of Omicron 3CLpro. Moreover by molecular dynamics simulation we demonstrated that currently available drugs acting as inhibitors of the SARS-CoV-2 main protease could be less effective in the case of Omicron variant due to the different chemical interactions in the binding site occurred after the recent amino acid mutations. Ultimately our study highlights the need of exploiting in silico and in vitro methods to discover novel 3CLpro inhibitors starting from the computationally based structure we presented herein and more in general to direct the major efforts to targeting the most conserved 3CLpro regions that appeared unchanged in the context of the Omicron variant.