Accurately predicting ligand binding affinities to their protein hosts with scoring functions remains one of the most significant challenges facing medicinal and biological chemists. One of the underappreciated reasons for this is the fact that individual protein-ligand non-covalent interactions are not always contributing to binding affinity in an additive fashion due to cooperativity. Cooperativity among ligand functional groups is the mutual modulation of the ligand's non-covalent interactions in such a way that the binding energy obtained from these interactions together is more (positive cooperativity) or less (negative cooperativity) than the sum of the binding energies obtained from them individually. In previous studies we revealed a positive ligand groups cooperativity between a hydrogen bond and aliphatic side chains for a series of thrombin inhibitors1, as well as a water-mediated positive cooperativity between a thermolysin inhibitor carboxyl group and an aliphatic side chain2. In the present study, using thrombin as a model system, we present different types of ligand functional groups cooperativity.  Also, we reveal how factors such as ligand rigidity, bioisosteric replacement of functional groups, and additional H-bonds can affect the magnitude of the cooperativity. Understanding the fundamental factors affecting cooperativity, and quantifying various ligand functional groups cooperativity as we are doing using model systems, is important for building an experimental foundation for the improvement of scoring functions.(1) Muley, L.; et al., J. Med. Chem., 53, 2126-2135 (2010)(2) Nasief, N.; et al., J. Med. Chem., 55, 8283-8302 (2012)

In-depth analysis for the cooperative contributions of ligand functional groups to binding using thrombin as a model system

246th National Meeting (2013)

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