8QGV
Human Carbonic Anhydrase I in complex with 4-(5-acetyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidin-4-yl)benzenesulfonamide
This is a non-PDB format compatible entry.
Summary for 8QGV
| Entry DOI | 10.2210/pdb8qgv/pdb |
| Descriptor | Carbonic anhydrase 1, ZINC ION, ethyl (4~{S})-6-methyl-2-oxidanylidene-4-(4-sulfamoylphenyl)-3,4-dihydro-1~{H}-pyrimidine-5-carboxylate, ... (4 entities in total) |
| Functional Keywords | carbonic anhydrase; sulfonamide, inhibitor, metalloenzyme, lyase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 58621.92 |
| Authors | Angeli, A.,Ferraroni, M. (deposition date: 2023-09-05, release date: 2024-09-11, Last modification date: 2025-03-26) |
| Primary citation | Aslan, H.,Renzi, G.,Angeli, A.,D'Agostino, I.,Ronca, R.,Massardi, M.L.,Tavani, C.,Carradori, S.,Ferraroni, M.,Governa, P.,Manetti, F.,Carta, F.,Supuran, C.T. Benzenesulfonamide decorated dihydropyrimidin(thi)ones: carbonic anhydrase profiling and antiproliferative activity. Rsc Med Chem, 15:1929-1941, 2024 Cited by PubMed Abstract: In the last decades, carbonic anhydrases (CAs) have become the top investigated innovative pharmacological targets and, in particular, isoforms IX and XII have been widely studied due to the evidence of their overexpression in hypoxic tumors. The frantic race to find new anticancer agents places the quick preparation of large libraries of putative bioactive compounds as the basis of a successful drug discovery and development programme. In this context, multi-component and, in general, one-step reactions are becoming very popular and, among them, Biginelli's reaction gave clean and easy-to-isolate products. Thus, we synthesized a series of Biginelli's products (10-17a-b) and similar derivatives (20-21) bearing the benzenesulfonamide moiety, which is known to inhibit CA enzymes. Through the stopped-flow technique, we were able to assess their ability to inhibit the targeted CAs IX and XII in the nanomolar range with promising selectivity over the physiologically relevant isoforms I and II. Crystallography studies and docking simulations helped us to gain insight into the interaction patterns established in the enzyme-inhibitor complex. From a chemical similarity-based screening of in-house libraries of compounds, a diphenylpyrimidine (23) emerged. The surprisingly potent inhibitory activity of 23 for CAs IX and XII along with its strong antiproliferative effect on two (triple-negative breast cancer MDA-MB-231 and glioblastoma U87MG) cell lines laid the foundation for further investigation, again confirming the key role of CAs in cancer. PubMed: 38911163DOI: 10.1039/d4md00101j PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.84 Å) |
Structure validation
Download full validation report
