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

Abstract

New chemical modalities in drug discovery include molecules belonging to the bRo5 chemical space. Because of their complex and flexible structure, bRo5 compounds often suffer from a poor solubility/permeability profile. Chameleonicity describes the capacity of a molecule to adapt to the environment through conformational changes; the design of molecular chameleons is a medicinal chemistry strategy simultaneously optimizing solubility and permeability. A default method to quantify chameleonicity in early drug discovery is still missing. Here we introduce Chamelogk, an automated, fast, and cheap chromatographic descriptor of chameleonicity. Moreover, we report measurements for 55 Ro5 and bRo5 compounds and validate our method with literature data. Then, selected case studies (macrocycles, nonmacrocyclic compounds, and PROTACs) are used to illustrate the application of Chamelogk in combination with lipophilicity (BRlogD) and polarity (Δ log k w IAM) descriptors. Overall, we show how Chamelogk deserves being included in property-based drug discovery strategies to design oral bioavailable bRo5 compounds.

Beyond Rule of Five and PROTACs in Modern Drug Discovery: Polarity Reducers, Chameleonicity, and the Evolving Physicochemical Landscape

“…Compounds where the ETR is below 1 exhibit shifts in their theoretical polarity, likely due to polar shielding, IMHB formation, or other phenomena meant to reduce the polarity (i.e., polarity reducers). These compounds showed higher flexibility (a finding similar to that of the Caron group) and comprised mostly PROTACs, although bRo5 subsets with low ETR also existed (Supporting Information Figure S7). ETR correlated with various polar groups and flexibility descriptors (Supporting Information Figure S8), suggestive of the influence of flexibility and/or polar groups to form IMHBs and reduce ETR.…”

“…Our findings uncovered key physicochemical relationships crucial for early drug development, explaining some of the complex behaviors of bRo5 compounds, such as the notable three-dimensional “chameleonicity” often observed in PROTACs. ,,, These findings will hopefully assist in enhanced drug design and refined assay utilization in pharmaceutical companies.…”

“…Some of these strategies include conformational shielding with bulky lipophilic groups, amide bond modifications, inducing IMHBs, and macrocyclization . Certain polar bRo5 compounds, like PROTACs, saquinavir, atazanavir, and ritonavir, can display adaptability between elongated forms in aqueous environments and compact, less polar shapes in nonpolar solvents due to IMHB-induced chameleonicity. ,,, This behavior, evident in simulations ,, and column-based studies, facilitates solubility and permeability. Some compounds, such as rifampicin, leverage static IMHB for polarity reduction, whereas molecules like paritaprevir and cyclosporin A combine both shielding and IMHBs.…”

“…Overall, the orally bioavailable FDA-approved drugs exhibited properties akin to those described according to the k-means analysis, with the more polar type 5 and 6 drugs exhibiting lower ETR values, reducing apparent polarity and achieving absorption. Saquinavir, a chameleonic , antiviral type 6 bRo5 compound, served as an example of a large, polar, nonmacrocyclic molecular chameleon achieving absorption due to its lower ETR (ETR of 0.55 meeting Table criteria). Ritonavir, a moderately sized polar compound that assumes multiple conformations, possibly due to IMHB formation, exhibited good absorption as supported by its reduced ETR (a trait critical for type 5 and 6 bRo5s).…”

“…Column chromatography or partitioning-based approaches like the experimental measure of exposed polarity (EPSA), , ChamElogD, BRLogD, lipophilicity permeability efficiency (LPE), and ChemLogk have been successful in evaluating and identifying compounds that achieve both solubility and permeability due to intramolecular hydrogen bond (IMHB) formation and flexibility induced chameleonicity. Nuclear magnetic resonance (NMR) conformational approaches and X-ray crystallographic techniques have also successfully identified molecular chameleons. − These approaches all shed light on the interplay of solubility, polarity, permeability, flexibility, and chameleonicity.…”