Macrocycles are similar to naturally derived cyclic structures that carry properties of peptides. However, macrocycles are more constrained and entropically favorable, thus having increased probability of binding than peptides. As a result, they are ideal for targeting protein-protein interactions (PPI), which have large interfaces that are more difficult to be targeted by small molecules. In fact, even though they can be big, macrocycles can still have druglikeness and potentially violate Lipinski’s Rule of Five due to the ring constraint. All these reasons make macrocycles interesting candidates in drug design. However, one of the biggest challenges in actual docking studies is the realistic generation of conformations. The cyclization of macrocycles makes this process especially difficult. We investigate the conformational generation together with fast Fourier transform (FFT) based sampling in order to develop protein macrocycle docking approach. This work serves as a benchmark for future computational drug design and discovery involving macrocycles and proteins.

Developing the benchmark for protein macrocycle docking

250th National Meeting (2015)

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