Rifampicin as an example of beyond-rule-of-5 compound: Ionization beyond water and lipophilicity beyond octanol/water

Ermondi, Giuseppe; Vallaro, Maura; Saame, Jaan; Toom, Lauri; Leito, Ivo; Ruiz, Rebeca; Caron, Giulia

doi:10.1016/j.ejps.2021.105802

Cited by 9 publications

(10 citation statements)

References 34 publications

(43 reference statements)

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“… [18] Similarly OWELAS and OWELUY are referred to hydrate forms of rifampicin but are neutral. Since very small amount of water are sufficient to guarantee the presence of the zwitterionic form[ 12 , 18 ] these two structures were discarded. Finally, 16 CSD entries were retained.…”

Section: Resultsmentioning

confidence: 99%

“…In this study we determined the NMR conformational ensembles of rifampicin in polar and nonpolar environment using a method that provides a realistic ensemble of conformers and compared the results with crystallographic structures retrieved from CSD. In particular, we focused on the intriguing intramolecular hydrogen bond (IMHB) network exhibited by the macrocycle also in relation with its ionization state recently experimentally characterized in nonpolar media [12] . To relate structural features with molecular properties, we calculated the polar surface area (SA‐3D‐PSA, a major determinant of cell permeability) for all the experimental conformations.…”

Section: Introductionmentioning

confidence: 99%

“…In particular, we focused on the intriguing intramolecular hydrogen bond (IMHB) network exhibited by the macrocycle also in relation with its ionization state recently experimentally characterized in nonpolar media. [12] To relate structural features with molecular properties, we calculated the polar surface area (SA‐3D‐PSA, a major determinant of cell permeability) for all the experimental conformations. From the analysis of SA‐3D‐PSA variation with the environment, in view of the permeability of rifampicin, we explored its potential chameleonicity.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…Besides n-octanol, which is characterized by combining the apolar aliphatic chain with the hydrogen-bond donor/acceptor function of the hydroxyl group, other organic solvents have been proposed as alternatives to imitate different physiological cell barriers, including chloroform/water, alkane/water, 1,2-dichloroethane/water, dibutyl ether/water, toluene/water and propylene glycol dipelargonate/ water. [18][19][20][21][22][23][24] In this context, the difference between two partition coefficients using common organic solvents (e.g., n-octanol and alkanes) and water as a polar phase has been employed to study the solubility of drugs. 25 Furthermore, the experimental alkane/ water and toluene/water partition systems have given insights into the 'chameleonic' properties of drugs whose chemical space is beyond the metrics of the rule-of-five, although experimental limitations that fall on the low solubility of compounds in alkane-type solvents may limit their application.…”

Section: Introductionmentioning

confidence: 99%

Prediction of toluene/water partition coefficients in the SAMPL9 blind challenge: assessment of machine learning and IEF-PCM/MST continuum solvation models

Zamora¹,

Viayna²,

Pinheiro³

et al. 2023

Phys. Chem. Chem. Phys.

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“…Although logPo/w is an essential property for the prediction of the ADME-Tox properties of new drugs, the n-octanol/water system is a simple surrogate to explore the partition of compounds in biological environments. Besides n-octanol, which is characterized by combining the apolar aliphatic chain with the hydrogen-bond donor/acceptor function of the hydroxyl group, other organic solvents have been proposed as alternatives to imitate different physiological cell barriers, including chloroform/water, alkane/water, 1,2-dichloroethane/water, dibutyl ether/water, toluene/water and propylene glycol dipelargonate/water [18][19][20][21][22][23][24]. In this context, the difference between two partition coefficients using common organic solvents (e.g., n-octanol and alkanes) and water as polar phase has been employed to study the solubility of drugs [25].…”

Section: Introductionmentioning

confidence: 99%

Prediction of Toluene/Water Partition Coefficient in the SAMPL9 Blind Challenge: Assessment of Machine Learning and IEF-PCM/MST Continuum Solvation Models

Zamora

Viayna

Pinheiro

et al. 2023

Preprint

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In recent years the use of partition systems other than the widely used biphasic n-octanol/water has received increased attention to gain insight into the molecular features that dictate the lipophilicity of compounds. Thus, the difference between n-octanol/water and toluene/water partition coefficients has proven to be a valuable descriptor to study the propensity of molecules to form intramolecular hydrogen bonds and exhibit chameleon-like properties that modulate solubility and permeability. In this context, this study reports the experimental toluene/water partition coefficients (logPtol/w) for a series of 16 drugs that were selected as an external test set in the framework of the Statistical Assessment of the Modeling of Proteins and Ligands (SAMPL) blind challenge. This external set has been used by the computational community to calibrate their methods in the current edition (SAMPL9) of this contest. Furthermore, the study also investigates the performance of two computational strategies for the prediction of logPtol/w. The first relies on the development of two machine learning (ML) models, which are built up by combining the selection of 11 molecular descriptors in conjunction with either multiple linear regression (MLR) and random forest regression (RFR) models to target a dataset of 252 experimental logPtol/w values. The second consists of the parametrization of the IEF-PCM/MST continuum solvation model from B3LYP/6-31G(d) calculations to predict the solvation free energies of 163 compounds in toluene and benzene. The performance of the ML and IEF-PCM/MST models has been calibrated against external test sets, including the compounds that define the SAMPL9 logPtol/w challenge. The results are used to discuss the merits and weaknesses of the two computational approaches.

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Rifampicin as an example of beyond-rule-of-5 compound: Ionization beyond water and lipophilicity beyond octanol/water

Cited by 9 publications

References 34 publications

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

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

Prediction of toluene/water partition coefficients in the SAMPL9 blind challenge: assessment of machine learning and IEF-PCM/MST continuum solvation models

Prediction of Toluene/Water Partition Coefficient in the SAMPL9 Blind Challenge: Assessment of Machine Learning and IEF-PCM/MST Continuum Solvation Models

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