Managing Experimental 3D Structures in the Beyond?Rule?of?5 Chemical Space: The Case of Rifampicin

The beyond-Rule-of-5 (bRo5) chemical space is a source of new oral drugs and includes large flexible compounds. Because their size conformational variability, bRo5 molecules assume different privileged conformations in the compartments human body, i. e., they can exhibit chameleonic properties. elucidation ensemble 3D structures explored by such under conditions therefore critical to check role played chameleonicity modulate cell permeability. Here we characterized ensembles rifampicin, drug, polar nonpolar solvents solid state. We performed NMR experiments, analyzed results with novel algorithm set-up pool ad hoc silico strategies investigate crystallographic retrieved from CSD. Moreover, polarity descriptor often related permeability (SA-3D-PSA) was calculated for all conformers its variation environment analyzed. Results showed that behavior rifampicin solution state not superposable. identification dynamic intramolecular hydrogen bonds be assessed spectroscopy but X-ray structures. SA-3D-PSA revealed IMHBs do provide Overall, this study highlights peculiarity which permeable probably because presence static devoid any behavior, proper analysis experimental