Submission Details
Molecule(s):
Cc1cc2oc3c(c(=O)c2cc1Cl)[C@@H](c1ccc(F)cc1)N(CCCO)C3=O
Cc1cc2oc3c(c(=O)c2cc1Cl)[C@@H](c1ccc(Cl)cc1)N(CCCO)C3=O
Cc1cc2oc3c(c(=O)c2cc1Cl)[C@@H](c1ccc(Br)cc1)N(CCCO)C3=O
Design Rationale:
Structure Based Drug Design (SBDD) A rational design based on target was used, taking as reference SARS-CoV-2 main protease chain A (PDB: 6YB7) and because it presents structural similarity (98.69 %) and identity (96. 08 %) with The octameric SARS-CoV main protease chain A (PDB:3IWM), using Smith-Waterman Sequence Alignment method; the last protein (chain A) was used to generate a pharmacophoric model and inhibit the protein-protein interaction of the protease, as screening criteria: one molecule per conformation, one hit per molecule and rotary bonds (0-6), 4 molecules were obtained from which, the Pipeline was developed, taking into account PAINS, Druglikeness (Lipinski, Veber, Egan, Ghose and Muegge) and structural alerts BRENKS, The level of toxicity was also taken into account, with criteria such as carcinogenicity, Human either-a-go-go inhibition and Ames mutagenesis, as well as the synthetic feasibility of the molecules. One molecule was discarded for not meeting Druglikeness criteria and binding to the hERG receptor, the other three molecules were identified as bioisosters. The programs Pocketquery, ZincPharmer, AdmetSAR and SwissADME, which are freesoftware, were used.
Other Notes:
The research was carried out jointly by Harold Mateo Mojica Urrego (GESACH: Group of studies in synthesis and applications of heterocyclic compounds) and Paula Andrea Mojica Jimenez (Research group in Natural Products in the area of computational chemistry). Affiliated to the National University of Colombia, Science Faculty, Pharmacy Department.