In Silico Tools to Extract the Drug Design Information Content of Degradation Data: The Case of PROTACs Targeting the Androgen Receptor.

Proteolysis-Targeting Chimeras (PROTACs) have recently emerged as a promising technology in the drug discovery landscape. Large interest in the degradation of the androgen receptor (AR) as a new anti-prostatic cancer strategy has resulted in several papers focusing on PROTACs against AR. This study explores the potential of a few in silico tools to extract drug design information from AR degradation data in the format often reported in the literature. After setting up a dataset of 92 PROTACs with consistent AR degradation values, we employed the Bemis-Murcko method for their classification. The resulting clusters were not informative in terms of structure-degradation relationship. Subsequently, we performed Degradation Cliff analysis and identified some key aspects conferring a positive contribution to activity, as well as some methodological limits when applying this approach to PROTACs. Linker structure degradation relationships were also investigated. Then, we built and characterized ternary complexes to validate previous results. Finally, we implemented machine learning classification models and showed that AR degradation for VHL-based but not CRBN-based PROTACs can be predicted from simple permeability-related 2D molecular descriptors.

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

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 kwIAM) descriptors. Overall, we show how Chamelogk deserves being included in property-based drug discovery strategies to design oral bioavailable bRo5 compounds.