Small-molecule drug design relies on the design of chemical compounds that strongly bind to disease-target proteins, while simultaneously possessing low affinity for non-target proteins, thereby exhibiting high selectivity. Minor chemical structure changes to the ligand molecule usually result in little change in the compound’s efficacy. Both the protein and compound molecules have some flexibility, helping to adapt to each other and reduce the effect of the change. However, in rare but interesting cases, a small change can lead to a large effect on compound affinity. We have designed over 1,200 chemical compounds that bind to the family of 12 structurally closely related human carbonic anhydrase enzymes, determined over 7,000 interactions, and discovered some cases where an insertion or change of a single atom in the compound molecule led to an unexpected effect on the compound’s affinity. For example, when a linking atom between cyclohexane and benzene was a sulfur atom, the affinity for the CA IX isozyme was a million-fold greater than when the linking group was SO 2 . In a different case, addition of a methyl group to the ligand molecule reduced the affinity by thousands of fold due to the steric hindrance between the ligand and protein molecules. The X-ray crystal structures of such compounds bound to several CA isozymes revealed the structural reasons underlying the thermodynamics of ligand binding.
Paketurytė-Latvė et al. (Sun,) studied this question.