Abstract

Structure-based drug design frequently operates under the assumption that a single holo structure is relevant. However, a large number of crystallographic examples clearly show that multiple conformations are possible. In those cases, the protein reorganization free energy must be known to accurately predict binding free energies for ligands. Only then can the energetic preference among these multiple protein conformations be utilized to design ligands with stronger binding potency and selectivity. Here, we present a computational method to quantify these protein reorganization free energies. We test it on two retrospective drug design cases, Abl kinase and HSP90, and illustrate how alternative holo conformations can be derisked and lead to large boosts in affinity. This method will allow computer-aided drug design to better support complex protein targets.

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.