biostudies-literatureUnknown9Spassov DSThe salt bridge is the strongest non-covalent interaction in nature and is known to participate in protein folding, protein-protein interactions, and molecular recognition. However, the role of salt bridges in the context of drug design has remained not well understood. Here, we report that a common feature in the mechanism of inhibition of the N-myristoyltransferases (NMT), promising targets for the treatment of protozoan infections and cancer, is the formation of a salt bridge between a positively charged chemical group of the small molecule and the negatively charged C-terminus of the enzyme. Substituting the inhibitor positively charged amine group with a neutral methylene group prevents the formation of the salt bridge and leads to a dramatic activity loss. Molecular dynamics simulatiFrontiers in molecular biosciences1066029https://www.ebi.ac.uk/biostudies/studies/S-EPMC9871453biostudies-literatureA role of salt bridges in mediating drug potency: A lesson from the N-myristoyltransferase inhibitors.PMC9871453Atanasova MDoytchinova ISpassov DSfalseA role of salt bridges in mediating drug potency: A lesson from the N-myristoyltransferase inhibitors.The salt bridge is the strongest non-covalent interaction in nature and is known to participate in protein folding, protein-protein interactions, and molecular recognition. However, the role of salt bridges in the context of drug design has remained not well understood. Here, we report that a common feature in the mechanism of inhibition of the N-myristoyltransferases (NMT), promising targets for the treatment of protozoan infections and cancer, is the formation of a salt bridge between a positively charged chemical group of the small molecule and the negatively charged C-terminus of the enzyme. Substituting the inhibitor positively charged amine group with a neutral methylene group prevents the formation of the salt bridge and leads to a dramatic activity loss. Molecular dynamics simulati2022-01-01T00:00:00Z20222025-04-26T13:15:15.046Z2024-11-20T11:06:53.395ZS-EPMC98714533670392010.3389/fmolb.2022.1066029