SARS-CoV-2 has a sequence identity of 79.6% with SARS-CoV-1 and 96.2% with bat coronavirus. From this high similarity in nucleotide sequences it was inferred that, like SARS-CoV-1, SARS-CoV-2 uses a highly glycosylated protein found in its envelope, called S-protein, to bind to the cell through interaction with the angiotensin-converting enzyme, ACE2 . The S-protein, made up of the S1 and S2 subunits, plays a crucial role during the first contact between the virus and the ACE2 receptor. The S1 subunit binds to ACE2 and the S2 subunit is activated by the protein serine protease TMPRSS2, which promotes membrane fusion and cell infection. Both SARS-CoV-1 and SARS-CoV-2 use ACE2 to enter host cells, so blocking this critical interaction would prevent the entry of the virus. The S1 subunit contains the so-called receptor binding domain, RBD, a fragment of it that is sufficient to bind to the peptidase domain of ACE2. Most studies have focused on this domain, because it binds to cell receptors and, in addition, is the main target of neutralizing antibodies during infection. In the present study we have carried out a virtual screening of S-protein inhibitors, focusing on the area of interaction between the RBD and the ACE2 protein. The screening has been done on two databases of molecular structures. On the one hand, Selleck FDA approved drugs 22 (FDA from now on), a database of FDA-approved drugs, and on the other Selleck database of Natural Products, (NAT from now on) database of natural compounds. We have included the flexibility of the protein through the study and subsequent clustering of classical molecular dynamics trajectories, and in addition, different docking methodologies have been used, such as those included in the Qvina and MOE programs. The use of the MOE program allows the use of a pharmacophore guided docking, for which two possible pharmacophores were defined: one focused on imitating the best interactions between the RBD of the SARS-CoV-2 protein-S and ACE2 (COV2-ACE2), and another focused on imitating the interactions that improve the most when moving from the RBD system of the SARS-CoV-1 and ACE2 protein-S to the SARS-CoV-2 plus ACE2 system. The second pharmacophore focuses, therefore, on trying to describe what changes occur in the RBD of SARS-CoV-2 versus SARS-CoV-1 so that the first binds with much greater affinity to ACE2. The results of these different dockings were be subjected to successively more computationally complex methodologies, so that a virtual screening process of a total set of 2791 compounds ended in a set 48, of which 10 were subjected to experimental tests.