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A Case Study on the Use of Binding Free Energies to Screen Inhibitors of Human Carbonic Anhydrase II

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The underlying dynamics of binding and unbinding of a ligand to an enzyme and its interactions with amino acid residues modify the enthalpy, entropy, and total binding free energy estimated using a single molecular dynamics trajectory in combination with the molecular mechanics with generalised Born and surface area solvation (MM/GBSA) method.


We present in this article a case study on the thermodynamics of binding to human carbonic anhydrase II (HCA II) by three well-known inhibitors, viz. (a) acetazolamide (AZM) that directly binds to the catalytic Zn(II) ion at the active site, (b) non-zinc binding 6-hydroxy-2-thioxocoumarin (FC5) (c) 2-[(S)-benzylsulfinyl]benzoic acid (3G1). In each case, the crystal structure or its analogue of inhibitor-bound HCA II has been used to perform classical molecular dynamics (MD) simulation in water till . AZM and FC5 are found to undergo repeated binding and unbinding with markedly different dynamics from the partially buried, substrate-binding hydrophobic pocket near the active site. 3G1, on the other hand, is found to remain mostly at its crystallographic binding site occluded from the active site of HCA II. The associated binding free energies ( ) have been computed using the known MM/GBSA method and compared to the available experimental data. Our results show that encounters several issues including limited sampling of multiple binding sites and incorrect prediction of the affinity of the chosen ligands. Possible use of the simulation results in further construction of Markov state models is also discussed.

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