“Cryptic” pockets are sites that are not visible on unliganded target proteins’ structures and only become apparent when a drug bind. They might offer a valid alternative to classical substrate-competitive sites in otherwise “undruggable” targets, but their hidden nature makes it difficult to use standard structure-based or computer-aided drug discovery approaches. What is more, the molecular mechanism by which cryptic sites are formed is still debated. Here, we investigate the nature of the cryptic sites harboured by seven diverse, pharmacologically relevant targets and compare the performance of different enhanced sampling approaches, including our recently-developed SWISH.<br/>Sampling water interfaces through scaled Hamiltonians (or SWISH) is a Hamiltonian-replica-exchange-based method that improves the sampling of hydrophobic cavities by scaling the interactions between water molecules and protein atoms. Our simulations, whose cumulative sampling time was more than 200 μs, help in clarifying the molecular mechanism of pocket formation and provide a solid basis for the choice of an efficient computational method. The induced-fit mechanism plays an important role in the opening of all the cryptic sites studied. Of the enhanced sampling methods tested, the combination of SWISH with small probes was the most efficient in exploring the cryptic sites.<br/>

Exploring cryptic pockets formation in targets of pharmaceutical interest with enhanced sampling simulations

2019 Spring National Meeting

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