Predicting ligand-protein binding affinity is a crucial element in the lead discovery and lead optimization processes. For a small molecule to become a drug, it needs to bind its molecular target strongly and selectively. Most medicinal chemists use computational methods, i.e. scoring functions, to predict ligand’s binding affinity. Unfortunately, these tools are still under-developed and their prediction to binding affinity is still questionable. This is mainly because they assume that the contribution of non-covalent interactions to binding affinity is additive. One of the binding driving factors that isn’t accounted for by scoring functions is cooperativity between different ligand functional groups. In this study, for the first time, a new type of cooperativity is revealed which is hydrophobic interaction-based cooperativity. In order to do that, two different series of thrombin inhibitors were designed where the difference between these series is that we systematically manipulated the ligand’s hydrophobic residues that bind to thrombin S2 and S3 pockets respectively. We found that there is a strong positive cooperativity between the P2 and P3 ligand's hydrophobic moieties accounts for -9.8 kJ/mole. Several factors contributed to that huge amount of cooperativity such as ligand conformational entropy, ligand functional group rigidity and ligand desolvation changes. Studies that investigate the intricate molecular aspects of protein-ligand binding are therefore crucial for the field of drug discovery.

Towards more explicit understanding of the binding molecular aspects: hydrophobic-based cooperativity among series of thrombin inhibitors

251st National Meeting (2016)

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