Going Viral: An Investigation into the Chameleonic Behaviour of Antiviral Compounds

Abstract

The ability to adjust conformations in response to the polarity of the environment, i.e. molecular chameleonicity, is considered to be important for conferring both high aqueous solubility and high cell permeability to drugs in chemical space beyond Lipinski's rule of 5. We determined the conformational ensembles populated by the antiviral drugs asunaprevir, simeprevir, atazanavir and daclatasvir in polar (DMSO-d 6 ) and non-polar (chloroform) environments with NMR spectroscopy. Daclatasvir was fairly rigid, whereas the first three showed large flexibility in both environments, that translated into major differences in solvent accessible 3D polar surface area within each conformational ensemble. No significant differences in size and polar surface area were observed between the DMSO-d 6 and chloroform ensembles of these three drugs. We propose that such flexible compounds are characterized as "partial molecular chameleons" and hypothesize that their ability to adopt conformations with low polar surface area contributes to their membrane permeability and oral absorption.

MicroED as a Powerful Tool for Structure Determination of Macrocyclic Drug Compounds Directly from Their Powder Formulations

“… The binding-site of NS3/4a is rather shallow and flat, making it difficult to target, and at the same time explains the open and flat conformation attained by simeprevir in this structure. Simeprevir has also been studied in solution; NMR ensembles in DMSO and chloroform revealed at least 15 different conformations, again demonstrating the flexibility span and gives an indication as to why it is so difficult to obtain crystals . Similar to pacritinib, the 0.85 Å MicroED structure of simeprevir (Figure ) displays two conformations in the asymmetric unit (Figure SI-4a).…”

Macrocycles in Drug Discovery─Learning from the Past for the Future

“…However, the majority of the oral macrocycles reside far into the bRo5 chemical space for several descriptors, i.e., MW, TPSA, and HBA. It is often assumed that compounds in the bRo5 space may achieve satisfactory cell permeability and solubility by behaving as molecular chameleons that adapt their conformations to the surrounding environment. , Experimental support for chameleonic behavior has been reported for several macrocyclic drugs in the bRo5 space, with cyclosporin being studied extensively and others such as roxithromycin, telithromycin, spiramycin, and simeprevir being investigated recently. ,, …”

“… 25 , 21 Experimental support for chameleonic behavior has been reported for several macrocyclic drugs in the bRo5 space, with cyclosporin being studied extensively and others such as roxithromycin, telithromycin, spiramycin, and simeprevir being investigated recently. 26 , 24 , 43 …”

“…25,21 Experimental support for chameleonic behavior has been reported for several macrocyclic drugs in the bRo5 space, with cyclosporin being studied extensively and others such as roxithromycin, telithromycin, spiramycin, and simeprevir being investigated recently. 26,24,43 By Principal Component Analysis. We used principal component analysis, an unsupervised machine learning method used to reduce the dimensionality of data, as an alternative way to probe the chemical space of the orally and parenterally administered macrocycles than by inspection of the descriptors of Lipinski's Ro5 and Veber's rule (Figure 7).…”

Chamelogk: A Chromatographic Chameleonicity Quantifier to Design Orally Bioavailable Beyond-Rule-of-5 Drugs

“…Indeed, NMR showed that the orientation of the side chains of telithromycin and roxithromycin varied between nonpolar and polar environments, confirming the crucial effect of macrocyclic side chains on chameleonicity . Recently, the same method has also been applied to PROTACs and nonmacrocyclic compounds (antivirals) . This approach has the advantage of focusing on true solution conformers, but it mainly remains a semiquantitative case-per-case investigation method.…”