Experimental Lipophilicity for Beyond Rule of 5 Compounds

Ermondi, Giuseppe; Vallaro, Maura; Goetz, Gilles H.; Shalaeva, Marina

doi:10.4155/fdd-2019-0002

Cited by 26 publications

(39 citation statements)

References 29 publications

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“…With weakened water binding, the intramolecular H-bond interactions may stabilize the structure in a folded form. In this way, negative enthalpy is consistent with the conformational flexibility of 'molecular chameleons' [26][27][28][29][30][31], and highlights the possible role of sorbed water influences on solubility.…”

Section: Enthalpy Of Solution Of Big Molecules Is Negativesupporting

confidence: 60%

“…A trend was evident in the log SEBM vs. nROT plot, suggesting that flexibility appears to enhance the solubility of big molecules. In the SGE model, a different lipophilicity scale might improve the performance of the approach, as empirically suggested in Figure 4c and as suggested by the chromatographic studies of Ermondi et al [27,28]. The introduction of a nonlinear H-bond basicity term in the case of the ABSOLV approach is empirical, and it is not clear how to relate it to first-principle thermodynamic treatment.…”

Section: Resultsmentioning

confidence: 99%

“…Lipophilicity of bRo5 compounds strongly depends on their chameleonic properties: closed form preferred in apolar environments and open form in aqueous media. It is suggested that a non-i n P r e s s traditional lipophilicity scale is needed for many bRo5 compounds, which takes into account the solute conformational flexibility and the polarity of the dissolution media [27,28]. Crystal structures of the big molecules and their 'hydration' in the solid state…”

Section: Factors That May Shed Light On the Unusual Intrinsic Aqueousmentioning

confidence: 99%

“…Many of the newly-approved therapeutics are used in immunosuppression, treatment of infectious/viral diseases, and in oncology. Since 2014, an increasing number of 'beyond the Rule of 5' (bRo5) commentaries have stressed that the strict adherence to the Ro5 may result in lost opportunities [21][22][23][24][25][26][27][28][29][30]. Cell-permeable and orally-bioavailable drugs can be discovered far into bRo5 chemical space.…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, concerns have been raised over the expected higher pharmacokinetic risks from bRo5 compounds: low solubility, poor cell permeability, increased cellular efflux, and extensive metabolism. Medicinal chemists have applied tactics to lessen some of the risks: (a) reducing or shielding polarity by N-methylation, or by bulky side chains, (b) selecting compounds with flexible rings structures allowing for conformational lability, and (c) selecting compounds which can reversibly form multiple intramolecular H-bonds (IMHB) to shield polar groups during passage across lipoidal cell barriers, in the manner of 'molecular chameleons' [26][27][28][29][30][31].…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Can small drugs predict the intrinsic aqueous solubility of ‘beyond Rule of 5’ big drugs?

Avdeef¹,

Kansy²

2020

ADMET DMPK

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The aim of the study was to explore to what extent small molecules (mostly from the Rule of 5 chemical space) can be used to predict the intrinsic aqueous solubility, S0, of big molecules from beyond the Rule of 5 (bRo5) space. It was demonstrated that the General Solubility Equation (GSE) and the Abraham Solvation Equation (ABSOLV) underpredict solubility in systematic but slightly ways. The Random Forest regression (RFR) method predicts solubility more accurately, albeit in the manner of a ‘black box.’ It was discovered that the GSE improves considerably in the case of big molecules when the coefficient of the log P term (octanol-water partition coefficient) in the equation is set to -0.4 instead of the traditional -1 value. The traditional GSE underpredicts solubility for molecules with experimental S0 < 50 µM. In contrast, the ABSOLV equation (trained with small molecules) underpredicts the solubility of big molecules in all cases tested. It was found that the errors in the ABSOLV-predicted solubilities of big molecules correlate linearly with the number of rotatable bonds, which suggests that flexibility may be an important factor in differentiating solubility of small from big molecules. Notably, most of the 31 big molecules considered have negative enthalpy of solution: these big molecules become less soluble with increasing temperature, which is compatible with ‘molecular chameleon’ behavior associated with intramolecular hydrogen bonding. The X‑ray structures of many of these molecules reveal void spaces in their crystal lattices large enough to accommodate many water molecules when such solids are in contact with aqueous media. The water sorbed into crystals suspended in aqueous solution may enhance solubility by way of intra-lattice solute-water interactions involving the numerous H‑bond acceptors in the big molecules studied. A ‘Solubility Enhancement–Big Molecules’ index was defined, which embodies many of the above findings.

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Section: Enthalpy Of Solution Of Big Molecules Is Negativesupporting

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Section: Factors That May Shed Light On the Unusual Intrinsic Aqueousmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Can small drugs predict the intrinsic aqueous solubility of ‘beyond Rule of 5’ big drugs?

Avdeef¹,

Kansy²

2020

ADMET DMPK

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Managing Experimental 3D Structures in the Beyond‐Rule‐of‐5 Chemical Space: The Case of Rifampicin

Ermondi

Lavore

Vallaro

et al. 2021

Chemistry A European J

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The beyond-Rule-of-5 (bRo5) chemical space is a source of new oral drugs and includes large and flexible compounds. Because of their size and conformational variability, bRo5 molecules assume different privileged conformations in the compartments of human body, i. e., they can exhibit chameleonic properties. The elucidation of the ensemble of 3D structures explored by such molecules under different conditions is therefore critical to check the role played by chameleonicity to modulate cell permeability. Here we characterized the conformational ensembles of rifampicin, a bRo5 drug, in polar and nonpolar solvents and in the solid state. We performed NMR experiments, analyzed their results with a novel algorithm and set-up a pool of ad hoc in silico strategies to investigate crystallographic structures retrieved from the CSD. Moreover, a polarity descriptor often related to permeability (SA-3D-PSA) was calculated for all the conformers and its variation with the environment analyzed. Results showed that the conformational behavior of rifampicin in solution and in the solid state is not superposable. The identification of dynamic intramolecular hydrogen bonds can be assessed by NMR spectroscopy but not by X-ray structures. Moreover, SA-3D-PSA revealed that dynamic IMHBs do not provide rifampicin with chameleonic properties. Overall, this study highlights that the peculiarity of rifampicin, which is cell permeable probably because of the presence of static IMHBs but is devoid of any chameleonic behavior, can be assessed by a proper analysis of experimental 3D structures.

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Predicting Solubility of Newly-Approved Drugs (2016–2020) with a Simple ABSOLV and GSE(Flexible-Acceptor) Consensus Model Outperforming Random Forest Regression

Avdeef¹,

Kansy²

2022

J Solution Chem

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This study applies the ‘Flexible-Acceptor’ variant of the General Solubility Equation, GSE( Φ,B ), to the prediction of the aqueous intrinsic solubility, log 10 S 0 , of FDA recently-approved (2016–2020) ‘small-molecule’ new molecular entities (NMEs). The novel equation had been shown to predict the solubility of drugs beyond Lipinski’s ‘Rule of 5’ chemical space (bRo5) to a precision nearly matching that of the Random Forest Regression (RFR) machine learning method. Since then, it was found that the GSE( Φ,B ) appears to work well not only for bRo5 NMEs, but also for Ro5 drugs. To put context to GSE( Φ,B ), Yalkowsky’s GSE(classic), Abraham’s ABSOLV, and Breiman’s RFR models were also applied to predict log 10 S 0 of 72 newly-approve NMEs, for which useable reported solubility values could be accessed (nearly 60% from FDA New Drug Application published reports). Except for GSE (classic), the prediction models were retrained with an enlarged version of the Wiki- pS 0 database (nearly 400 added log 10 S 0 entries since our recent previous study). Thus, these four models were further validated by the additional independent solubility measurements which the newly-approved drugs introduced. The prediction methods ranked RFR ~ GSE ( Φ,B ) > ABSOLV > GSE (classic) in performance. It was further demonstrated that the biases generated in the four separate models could be nearly eliminated in a consensus model based on the average of just two of the methods: GSE ( Φ,B ) and ABSOLV. The resulting consensus prediction equation is simple in form and can be easily incorporated into spreadsheet calculations. Even more significant, it slightly outperformed the RFR method.

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Experimental Lipophilicity for Beyond Rule of 5 Compounds

Cited by 26 publications

References 29 publications

Can small drugs predict the intrinsic aqueous solubility of ‘beyond Rule of 5’ big drugs?

Can small drugs predict the intrinsic aqueous solubility of ‘beyond Rule of 5’ big drugs?

Managing Experimental 3D Structures in the Beyond‐Rule‐of‐5 Chemical Space: The Case of Rifampicin

Predicting Solubility of Newly-Approved Drugs (2016–2020) with a Simple ABSOLV and GSE(Flexible-Acceptor) Consensus Model Outperforming Random Forest Regression

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