Search for Specific Inhibitors Targeting Type IA Topoisomerases.

Abstract

The type IA topoisomerase subfamily includes bacterial topoisomerase I and topoisomerase III encoded by topA and topB genes, reverse gyrase found in thermophilic bacteria and archaea, as well as eukaryotic topoisomerase III. Type IA topoisomerases also act on RNA as substrate. Important functions in neurological development have been demonstrated for human TOP3B. Type IA topoisomerase present in all bacterial pathogens should be a novel target that can be utilized for the discovery of new antibacterial agents. Naturally produced bacterial toxins have been shown to inhibit cell growth by targeting topoisomerase I. Topoisomerase III in human and other eukaryotes could potentially also be targeted for treatment of cancer and viral or parasitic infections. Docking, machine-learning, enzyme or cell-based screening campaigns have identified compounds that can inhibit the catalytic activity of type IA topoisomerases, or poisons that can trap the covalent complex of the targeted type IA topoisomerase. Small molecule inhibitors identified thus far for bacterial topoisomerase I or human TOP3B have not been viable candidates as drug leads mostly due to lack of sufficient potency and selectivity. The barriers for obtaining better inhibitors include the lack of an X-ray or cryo-EM structure of topoisomerase-ligand complex and mutations in the topoisomerase gene that can confirm the topoisomerase as primary cellular target. Well-designed combination of virtual and experiment screening to explore large chemical space in future studies may improve the likelihood of success for identifying small molecule inhibitors of type IA topoisomerases that can form specific protein-ligand complexes amenable for structure determination.