| 1. |
- Apprato, Giulia, et al.
(author)
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Exploring the chemical space of orally bioavailable PROTACs
- 2024
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In: Drug Discovery Today. - : Elsevier. - 1359-6446 .- 1878-5832. ; 29:4
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Research review (peer-reviewed)abstract
- 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 cuttingedge experimental, computational and hybrid design strategies based on 3D descriptors, which show promise for enhancing the probability of discovering PROTACs with high oral bioavailability.
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| 2. |
- Caron, Giulia, et al.
(author)
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Intramolecular hydrogen bonding : An opportunity for improved design in medicinal chemistry
- 2019
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In: Medicinal research reviews (Print). - : Wiley. - 0198-6325 .- 1098-1128. ; 39:5, s. 1707-1729
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Research review (peer-reviewed)abstract
- Recent literature shows that intramolecular hydrogen bond (IMHB) formation can positively impact upon the triad of permeability, solubility, and potency of drugs and candidates. IMHB modulation can be applied to compounds in any chemical space as a means for discovering drug candidates with both acceptable potency and absorption, distribution, metabolism, and excretion-Tox profiles. Integrating IMHB formation in design of drugs is, therefore, an exciting and timely challenge for modern medicinal chemistry. In this review, we first provide some background about IMHBs from the medicinal chemist's point of view and highlight some IMHB-associated misconceptions. Second, we propose a classification of IMHBs for drug discovery purposes, review the most common in silico tactics to include IMHBs in lead optimization and list some experimental physicochemical descriptors, which quantify the propensity of compounds to form IMHBs. By focusing on the compounds size and the number of IMHBs that can potentially be formed, we also outline the major difficulties encountered when designing compounds based on the inclusion of IMHBs. Finally, we discuss recent case studies illustrating the application of IMHB to optimize cell permeability and physicochemical properties of small molecules, cyclic peptides and macrocycles.
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| 3. |
- Caron, Giulia, et al.
(author)
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Steering New Drug Discovery Campaigns : Permeability, Solubility, and Physicochemical Properties in the bRo5 Chemical Space
- 2021
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In: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 12:1, s. 13-23
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Journal article (peer-reviewed)abstract
- An increasing number of drug discovery programs concern compounds in the beyond rule of 5 (bRo5) chemical space, such as cyclic peptides, macrocycles, and degraders. Recent results show that common paradigms of property-based drug design need revision to be applied to larger and more flexible compounds. A virtual event entitled "Solubility, permeability and physico-chemical properties in the bRo5 chemical space" was organized to provide preliminary guidance on how to make the discovery of oral drugs in the bRo5 space more effective. The four speakers emphasized the importance of the bRo5 space as a source of new oral drugs and provided examples of experimental and computational methods specifically tailored for design and optimization in this chemical space.
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| 4. |
- Ermondi, Giuseppe, et al.
(author)
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Conformational Sampling Deciphers the Chameleonic Properties of a VHL-Based Degrader
- 2023
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In: Pharmaceutics. - : MDPI. - 1999-4923. ; 15:1
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Journal article (peer-reviewed)abstract
- 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. Here, we employ PROTAC-1 (a passively cell-permeable degrader), for which NMR and physicochemical data prove the chameleonic behaviour, to benchmark the capacity of two conformational sampling algorithms and selection schemes. To characterize the conformational ensembles in both polar and nonpolar environments, we compute three molecular properties proven to be essential for cell permeability: conformer shape (radius of gyration), polarity (3D PSA), and the number of intramolecular hydrogen bonds. Energetic criteria were also considered. Infographics monitored the simultaneous variation of those properties in computed and NMR conformers. Overall, we provide key points for tuning conformational sampling tools to reproduce PROTAC-1 chameleonicity according to NMR evidence. This study is expected to improve the design of PROTAC drugs and the development of computational sustainable strategies to exploit the potential of new modalities in drug discovery.
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| 5. |
- Ermondi, Giuseppe, et al.
(author)
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Solubility prediction in the bRo5 chemical space : where are we right now?
- 2020
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In: ADMET and DMPK. - : International Association of Physical Chemists (IAPC). - 1848-7718. ; 8:3, s. 207-214
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Journal article (peer-reviewed)abstract
- Modelling the solubility of compounds in the "beyond Rule of 5" (bRo5) chemical space is in its infancy and to date only a few studies have been reported in the literature. Based on our own results, and those already published, we conclude that consideration of conformational flexibility and chameleon like behaviour is important, but quantitative models that account for these properties remain to be developed. Inclusion of 3D information appears to be somewhat less important than for cell permeability and extremely challenging due to the difficulties of accurate conformational sampling in the bRo5 space. Currently, methods for modelling of solubility will have to be tailored to the set of investigated compounds.
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| 6. |
- Poongavanam, Vasanthanathan, et al.
(author)
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Predicting the permeability of macrocycles from conformational sampling – limitations of molecular flexibility
- 2020
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In: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 110:1, s. 301-313
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Journal article (peer-reviewed)abstract
- Macrocycles constitute superior ligands for targets that have flat binding sites but often require long synthetic routes, emphasizing the need for property prediction prior to synthesis. We have investigated the scope and limitations of machine learning classification models and of regression models for predicting the cell permeability of a set of de novo-designed, drug-like macrocycles. 2D-Based classification models, which are fast to calculate, discriminated between macrocycles that had low-medium and high permeability and may be used as virtual filters in early drug discovery projects. Importantly, stereo- and regioisomer were correctly classified. QSPR studies of two small sets of comparator drugs suggested that use of 3D descriptors, calculated from biologically relevant conformations, would allow development of more precise regression models for late phase drug projects. However, a 3D permeability model could only be developed for a rigid series of macrocycles. Comparison of NMR based conformational analysis with in silico conformational sampling indicated that this shortcoming originates from the inability of the molecular mechanics force field to identify the relevant conformations for flexible macrocycles. We speculate that a Kier flexibility index of ≤10 constitutes a current upper limit for reasonably accurate 3D prediction of macrocycle cell permeability.
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| 7. |
- Sebastiano, Matteo Rossi, et al.
(author)
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Impact of Dynamically Exposed Polarity on Permeability and Solubility of Chameleonic Drugs Beyond the Rule of 5
- 2018
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 61:9, s. 4189-4202
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Journal article (peer-reviewed)abstract
- Conformational flexibility has been proposed to significantly affect drug properties outside rule-of-5 (Ro5) chemical space. Here, we investigated the influence of dynamically exposed polarity on cell permeability and aqueous solubility for a structurally diverse set of drugs and clinical candidates far beyond the Ro5, all of which populated multiple distinct conformations as revealed by X-ray crystallography. Efflux-inhibited (passive) Caco-2 cell permeability correlated strongly with the compounds’ minimum solvent-accessible 3D polar surface areas (PSA), whereas aqueous solubility depended less on the specific 3D conformation. Inspection of the crystal structures highlighted flexibly linked aromatic side chains and dynamically forming intramolecular hydrogen bonds as particularly effective in providing “chameleonic” properties that allow compounds to display both high cell permeability and aqueous solubility. These structural features, in combination with permeability predictions based on the correlation to solvent-accessible 3D PSA, should inspire drug design in the challenging chemical space far beyond the Ro5.
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