Abstract
Human topoisomerase III beta (TOP3B) is a type IA topoisomerase that can change the topology of DNA and RNA substrates via a phosphotyrosine covalent intermediate. TOP3B has been shown to be required for the efficient replication of certain positive-sense ssRNA viruses including Dengue. We applied molecular dynamics simulation combined with docking studies to identify potential inhibitors of TOP3B from a library comprised of drugs that are FDA-approved or undergoing clinical trials for potential drug repurposing. Topoisomerase activity assay of the top virtual screening hits showed that bemcentinib, a compound known to target the AXL receptor tyrosine kinase, can inhibit TOP3B relaxation activity. Additional small molecules that share the N5,N3-1H-1,2,4-triazole-3,5-diamine moiety of bemcentinib were synthesized and tested for inhibition of TOP3B relaxation activity. Five of these molecules showed comparable IC(50) as bemcentinib for inhibition of TOP3B. However, these five molecules had less selectivity towards TOP3B inhibition versus bemcentinib when inhibition of the type IB human topoisomerase I was com-pared. These results suggest that exploration of tyrosine kinase inhibitors and their analogs may allow the identification of novel topoisomerase inhibitors.