For certain applications, it is desirable to discover small molecules that lock a protein in a given conformation, however virtual screening by molecular docking has not yet met this challenge. In this work, we discuss this problem and the problem of flexible receptor docking. The biggest challenges in flexible receptor docking are to compare the receptor energies between different states and to not overfit the receptor, docking to an unrealistic receptor conformation that does not yield new ligands during a prospective screen. These challenges will be discussed, along with algorithmic solutions for fast molecular docking screening and applications to new small molecule discovery in some systems. The potential and future of this method will be discussed.

Algorithms for discovering small molecules that stabilize specific protein conformations

245th National Meeting (2013)

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