In silico screening-based discovery of inhibitors against glycosylation proteins dysregulated in cancer.

Targeting enzymes associated with the biosynthesis of aberrant glycans is an under-utilized strategy in discovering potential inhibitors or drugs against cancer. The formation of cancer-associated glycans is mainly due to the dysregulated expression of glycosyltransferases and glycosidases, which play crucial roles in maintaining cellular structure and function. We screened a database of more than 14,000 compounds consisting of natural products and drugs for inhibition against four glycosylation enzymes - Alpha1-6FucT, ST6Gal1, ERMan1, and GlcNAcT-V. The top inhibitors identified against each enzyme were subsequently analyzed for potential binding against all four enzymes. In silico screening results show several promising candidates that could potentially inhibit all four enzymes: (1) Amb20622156 (demethylwedelolactone) [ERMan1: -9.3 kcal/mol; Alpha1-6FucT: -7.3 kcal/mol; ST6Gal1: -8.4 kcal/mol; GlcNAcT-V: -7.2 kcal/mol], (2) Amb22173588 (1,2-dihydrotanshinone I) [ERMan1: -9.3 kcal/mol; Alpha1-6FucT: -6.1 kcal/mol; ST6Gal1: -9.2 kcal/mol; GlcNAcT-V: -7.9 kcal/mol], and (3) Amb22173591 (tanshinol B) [ERMan1: -9.3 kcal/mol; Alpha1-6FucT: -6.0 kcal/mol; ST6Gal1: -9.8 kcal/mol; GlcNAcT-V: -7.7 kcal/mol]. Drug-enzyme active site residue interaction analyses show that the putative inhibitors form non-covalent bonding interactions with key active site residues in each enzyme, suggesting critical target residues in the four enzymes' active sites. Furthermore, pharmacokinetic property prediction analysis using pkCSM indicates that all of these inhibitors have good ADMETox properties (i.e., log P < 5, Caco-2 permeability > 0.90, intestinal absorption > 30%, skin permeability>-2.5, CNS permeability <-3, maximum tolerated dose < 0.477, minnow toxicity<-0.3). The in silico docking approach to glycosylation enzyme inhibitor prediction could help guide and streamline the discovery of novel inhibitors against enzymes involved in aberrant protein glycosylation.Communicated by Ramaswamy H. Sarma.