Implications of promiscuous Pim-1 kinase fragment inhibitor hydrophobic interactions for fragment-based drug design

Journal of Medicinal Chemistry
Andrew C GoodRonnie R Wei

Abstract

We have studied the subtleties of fragment docking and binding using data generated in a Pim-1 kinase inhibitor program. Crystallographic and docking data analyses have been undertaken using inhibitor complexes derived from an in-house surface plasmon resonance (SPR) fragment screen, a virtual needle screen, and a de novo designed fragment inhibitor hybrid. These investigations highlight that fragments that do not fill their binding pocket can exhibit promiscuous hydrophobic interactions due to the lack of steric constraints imposed on them by the boundaries of said pocket. As a result, docking modes that disagree with an observed crystal structure but maintain key crystallographically observed hydrogen bonds still have potential value in ligand design and optimization. This observation runs counter to the lore in fragment-based drug design that all fragment elaboration must be based on the parent crystal structure alone.

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Citations

Dec 4, 2012·International Journal of Molecular Sciences·Zorik ChilingaryanAaron J Oakley
Jun 26, 2013·Future Medicinal Chemistry·Rocco CaliandroCosimo Damiano Altomare
Aug 20, 2016·Journal of Enzyme Inhibition and Medicinal Chemistry·Bassem H Naguib, Hala B El-Nassan
Oct 26, 2016·Journal of Computer-aided Molecular Design·Ashutosh Kumar, Kam Y J Zhang
Jan 21, 2015·Bioorganic & Medicinal Chemistry Letters·Ryan P WurzAndrew S Tasker
Mar 25, 2019·Journal of Cheminformatics·Célien JacquemardEsther Kellenberger
May 29, 2021·Frontiers in Chemistry·Simone Di MiccoGiuseppe Bifulco
Aug 19, 2017·Journal of Medicinal Chemistry·Panagiotis K ChrysanthopoulosSally-Ann Poulsen

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