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 in silico 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. Then, we utilized experimental data to validate our novel computational strategies based on tools crafted to encompass a spectrum of complexities and innovative features. After confirming that the formation of IMHBs is the primary driving factor behind chameleonicity, we initially utilized conformational sampling data to define cChameCS, an IMHB-mediated, simple, and rapid chameleonicity predictor index suitable for early drug discovery. Subsequently, we identified dynamic IMHB patterns relevant to chameleonicity through molecular dynamics simulations. Finally, we proposed a workflow for designing structurally related chameleonic PROTACs of potential application in the lead optimization process.

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. Subsequently, we describe cutting-edge experimental, computational and hybrid design strategies based on 3D descriptors, which show promise for enhancing the probability of discovering PROTACs with high oral bioavailability.

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.

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. Macrocycles usually reside in the beyond the Rule of 5 chemical space, but 30-40% of the drugs and clinical candidates are orally bioavailable. Simple bi-descriptor models, i.e., HBD ≤ 7 in combination with either MW < 1000 Da or cLogP > 2.5, distinguished orals from parenterals and can be used as filters in design. We propose that recent breakthroughs in conformational analysis and inspiration from natural products will further improve the de novo design of macrocycles.

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. To reproduce the experimental information content, we generated conformer ensembles with conformational sampling and molecular dynamics in both water and nonpolar solvents. Then we calculated Rgyr, 3D PSA, and IMHB number. An innovative pool of strategies for data analysis was then provided. Overall, we report a contribution to close the gap between experimental and computational methods for characterizing bRo5 physicochemical properties.

Designing Soluble PROTACs: Strategies and Preliminary Guidelines.

Solubility optimization is a crucial step to obtaining oral PROTACs. Here we measured the thermodynamic solubilities (log S) of 21 commercial PROTACs. Next, we measured BRlogD and log kwIAM (lipophilicity), EPSA, and Δ log kwIAM (polarity) and showed that lipophilicity plays a major role in governing log S, but a contribution of polarity cannot be neglected. Two-/three-dimensional descriptors calculated on conformers arising from conformational sampling and steered molecular dynamics failed in modeling solubility. Infographic tools were used to identify a privileged region of soluble PROTACs in a chemical space defined by BRlogD, log kwIAM and topological polar surface area, while machine learning provided a log S classification model. Finally, for three pairs of PROTACs we measured the solubility, lipophilicity, and polarity of the building blocks and identified the limits of estimating PROTAC solubility from the synthetic components. Overall, this paper provides promising guidelines for optimizing PROTAC solubility in early drug discovery programs.

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. For comparison purposes, the same procedure was applied to a dataset of about 50 bRo5 approved drugs reported in the literature. Correlation matrices, PCAs, box plots, and other graphical tools were used to define and understand the chemical space covered by PROTACs and building blocks in relation to other compounds. Results show that linkers have different properties than E3 ligands and warheads. Polar descriptors additivity is not respected when passing from building blocks to degraders. Moreover, a very preliminary analysis based on three PROTACs with high, intermediate, and low permeability showed how the most permeable compounds seem to occupy a region closer to bRo5 drugs and, thus, exhibit different properties than impermeable compounds. Finally, a second database, PROTACpedia, was used to discuss the relevance of physicochemical descriptors on degradation activity.