Molecular properties, including chameleonicity, as essential tools for designing the next generation of oral beyond rule of five drugs.

Background And Purpose: The classical drug discovery toolbox continually expands beyond traditional rule of five (Ro5)-compliant small molecules to include new chemical modalities for difficult-to-drug targets. The paper focuses on the molecular properties essential to drive oral bioavailability within the bRo5 framework.

Experimental Approach: The first part outlines the concept and methodologies for characterizing bRo5 physicochemical properties, including considerations on chameleonicity; in particular, the paper summarizes the content of the last author's talk presented during the IAPC-10 Meeting held in Belgrade in September 2023 (https://iapchem.

IMHB-Mediated Chameleonicity in Drug Design: A Focus on Structurally Related PROTACs.

Molecular chameleonicity may enable compounds to compensate for the unfavorable ADME properties typically associated with complex molecules, such as PROTACs. Here we present a few strategies to implement chameleonicity considerations in drug design. Initially, we identified six structurally related CRBN-based PROTACs targeting BET proteins and experimentally verified whether chameleonicity is needed to obtain an acceptable physicochemical profile.

Exploring the chemical space of orally bioavailable PROTACs.

A principal challenge in the discovery of proteolysis targeting chimeras (PROTACs) as oral medications is their bioavailability. To facilitate drug design, it is therefore essential to identify the chemical space where orally bioavailable PROTACs are more likely to be situated. To this aim, we extracted structure-bioavailability insights from published data using traditional 2D descriptors, thereby shedding light on their potential and limitations as drug design tools.

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.

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

We have analyzed FDA-approved macrocyclic drugs, clinical candidates, and the recent literature to understand how macrocycles are used in drug discovery. Current drugs are mainly used in infectious disease and oncology, while oncology is the major indication for the clinical candidates and in the literature Most macrocyclic drugs bind to targets that have difficult to drug binding sites. Natural products have provided 80-90% of the drugs and clinical candidates, whereas macrocycles in ChEMBL have less complex structures.

Conformational Sampling Deciphers the Chameleonic Properties of a VHL-Based Degrader.

Chameleonicity (the capacity of a molecule to adapt its conformations to the environment) may help to identify orally bioavailable drugs in the beyond-Rule-of-5 chemical space. Computational methods to predict the chameleonic behaviour of degraders have not yet been reported and the identification of molecular chameleons still relies on experimental evidence. Therefore, there is a need to tune predictions with experimental data.

Refinement of Computational Access to Molecular Physicochemical Properties: From Ro5 to bRo5.

There is a need of computational tools to rank bRo5 drug candidates in the very early phases of drug discovery when chemical matter is unavailable. In this study, we selected three compounds: (a) a Ro5 drug (Pomalidomide), (b) a bRo5 orally available drug (Saquinavir), and (c) a polar PROTAC (CMP 98) to focus on computational access to physicochemical properties. To provide a benchmark, the three compounds were first experimentally characterized for their lipophilicity, polarity, IMHBs, and chameleonicity.

Designing Soluble PROTACs: Strategies and Preliminary Guidelines.

Solubility optimization is a crucial step to obtaining oral PROTACs. Here we measured the thermodynamic solubilities (log ) of 21 commercial PROTACs. Next, we measured BRlogD and log (lipophilicity), EPSA, and Δ log (polarity) and showed that lipophilicity plays a major role in governing log , but a contribution of polarity cannot be neglected.

Are we ready to design oral PROTACs®?

PROTACs® are expected to strongly impact the future of drug discovery. Therefore, in this work we firstly performed a statistical study to highlight the distribution of E3 ligases and POIs collected in PROTAC-DB, the main online database focused on degraders. Moreover, since the emerging technology of protein degradation deals with large and complex chemical structures, the second part of the paper focuses on how to set up a property-based design strategy to obtain oral degraders.

Rational Control of Molecular Properties Is Mandatory to Exploit the Potential of PROTACs as Oral Drugs.

To obtain new oral drugs in the beyond rule of five space, PROTACs among others, molecular properties should be optimized in early drug discovery. Degraders call for design strategies which focus on intramolecular interaction and chameleonicity. In parallel, tailored revalidation of permeability assessment and prediction methods becomes fundamental in this innovative chemical space.

PROTACs and Building Blocks: The 2D Chemical Space in Very Early Drug Discovery.

Targeted protein degradation by PROTACs has emerged as a new modality for the knockdown of a range of proteins, and, more recently, it has become increasingly clear that the PROTAC chemical space requires characterization through a pool of ad hoc physicochemical descriptors. In this study, a new database named PROTAC-DB that provides extensive information about PROTACs and building blocks was used to obtain the 2D chemical structures of about 1600 PROTACs, 60 E3 ligands, 800 linkers, and 202 warheads. For every structure, we calculated a pool of seven 2D descriptors carefully identified as informative for large and flexible structures.