Authors
Henrik Möbitz
Published in
Chimia. Volume 80. Issue 7-8. Pages 464-472. Aug 19, 2026. Epub Aug 19, 2026.
Abstract
This manuscript traces my journey through computational medicinal chemistry, showing how mechanistic and structural insights and physicochemical reasoning enable the translation of challenging targets into drugs and general design principles. The central theme, conformational analysis, links on-target potency via pre-organization of the bioactive conformation with physics-based physicochemical property prediction. This strategy can unlock dramatic gains in lipophilic efficiency and pharmacokinetic properties through the judicious addition of single atoms. This principle is extended to proteins, particularly kinases, where discrete conformational states can explain binding modes and kinetics. Binding to inactive conformations is linked to slow-on/ slow-off kinetics and can be engineered through ligand design or protein mutations. The manuscript summarizes principles of oral bioavailability in beyond-Rule-of-5 (bRo5) space, highlighting neutral polarity as a key determinant of permeability and exposure. Marketed oral bRo5 drugs and the lead optimization campaigns of first in class representatives converge on a polarity-lipophilicity sweet spot. Finally, nonclassical zwitterions represent a general design strategy to reconcile low lipophilicity with high permeability, supported by strong agreement between computation and experiment.
PMID:
42633625
Bibliographic data and abstract were imported from PubMed on 24 Aug 2026.
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