Webinar Archives

Nov 15

Designing Macrocycles using Schrödinger Tools

Dr. Tatjana Braun

Senior Scientist, Application Sciences

Macrocycles are structurally diverse and have a wide range of physicochemical properties and promising biological activities. These characteristics have made them an important and growing class of clinical drug candidates. However, macrocycles are often more difficult to work with than typical drug-like small molecules, both synthetically and computationally. 

Here, we want to present a toolkit for computational macrocycle design introduced by Schrödinger over the last few years. Key component is a new macrocycle sampling approach based on established protein structure prediction algorithms that has shown excellent accuracy, robustness, and speed on a diverse benchmarking data set of 208 macrocycles. 

The new sampling technology is at the core of a variety of macrocyclic workflows:  macrocycle bioactive conformer stability calculation, membrane permeability predictions2, and binding mode determination using ligand-receptor docking with Glide. 

In addition, we have extended the scope of applicability of FEP+ to include relative binding free energy calculations between macrocycles with different ring sizes and between macrocycles and their corresponding acyclic counterparts. 

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