The Critical Role of Passive Permeability in Designing Successful Drugs

Di, Li; Artursson, Per; Avdeef, Alex; Benet, Leslie Z.; Houston, J. Brian; Kansy, Manfred; Kerns, Edward H.; Lennernäs, Hans; Smith, Dennis A.; Sugano, Kiyohiko

doi:10.1002/cmdc.202000419

Cited by 65 publications

(54 citation statements)

References 104 publications

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“…Cell permeability is also required for compounds to be absorbed after oral administration. 4 Interestingly, some studies have found that macrocyclization can result in major increases in cell permeability, 5 , 6 while others have found only a limited increase 7 , 8 or a reduction in permeability upon macrocyclization. 9 …”

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confidence: 99%

Cell Permeability of Isomeric Macrocycles: Predictions and NMR Studies

Begnini

Poongavanam

Atilaw

et al. 2021

ACS Med. Chem. Lett.

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Conformation-dependent 3D descriptors have been shown to provide better predictions of the physicochemical properties of macrocycles than 2D descriptors. However, the computational identification of relevant conformations for macrocycles is nontrivial. Herein, we report that the Caco-2 cell permeability difference between a pair of diastereomeric macrocycles correlated with their solvent accessible 3D polar surface area and radius of gyration. The descriptors were calculated from the macrocycles’ solution-phase conformational ensembles and independently from ensembles obtained by conformational sampling. Calculation of the two descriptors for three other stereo- and regioisomeric macrocycles also allowed the correct ranking of their cell permeability. Methods for conformational sampling may thus allow ranking of passive permeability for moderately flexible macrocycles, thereby contributing to the prioritization of macrocycles for synthesis in lead optimization.

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mentioning

confidence: 99%

Cell Permeability of Isomeric Macrocycles: Predictions and NMR Studies

Begnini

Poongavanam

Atilaw

et al. 2021

ACS Med. Chem. Lett.

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“…Physical chemistry plays a central role in oral drug absorption [86]. In addition, physical chemistry is also important for hepatic clearance, renal clearance, and tissue distribution (including the brain) [85,[168][169][170][171][172][173][174][175][176]. A recent survey suggested that a poor understanding of physical chemistry is one of the reasons for the prediction failure of OA PBPK modelling [6].…”

Section: The Critical Role Of Physical Chemistry In Oa-pbpk Modellingmentioning

confidence: 99%

Lost in modelling and simulation?

Sugano

2021

ADMET DMPK

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Over the past few decades, physiologically-based pharmacokinetic modelling (PBPK) has been anticipated to be a powerful tool to improve the productivity of drug discovery and development. However, recently, multiple systematic evaluation studies independently suggested that the predictive power of current oral absorption (OA) PBPK models needs significant improvement. There is some disagreement between the industry and regulators about the credibility of OA PBPK modelling. Recently, the editorial board of AMDET&DMPK has announced the policy for the articles related to PBPK modelling (Modelling and simulation ethics). In this feature article, the background of this policy is explained: (1) Requirements for scientific writing of PBPK modelling, (2) Scientific literacy for PBPK modelling, and (3) Middle-out approaches. PBPK models are a useful tool if used correctly. This article will hopefully help advance the science of OA PBPK models.

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“…MW, nHBA and nHBA: The molecular weight (MW) plays a pivotal role in the drug action: the higher the MW (500 g/mol ≤ MW), the poorer the absorption and bioavailability 35 . The MW of phytol and 3-tetradecyn-1-ol were calculated and the results are shown in Table 3.…”

Section: Fig 1: a Gc-ms Chromatogram Peak Profile Of Methanolic Encephalartos Ferox Fruit Extractmentioning

confidence: 99%

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2021

IJPSR

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The constant increase in the emergence of multidrug resistance among Staphylococcus aureus strains threatens public health. The study aimed at evaluating the anti-S. aureus activity, pharmacokinetic properties and interactions of compounds from Erianthemum dregei with proteins in S. aureus. Anti-S. aureus activity was investigated by broth dilution method while gas chromatography-mass spectrometry (GC-MS) was used to identify the compounds. The drug-likeness, pharmacokinetic and toxicity profiles of the compounds were predicted by SwissADME and PreADMET tools. AutoDock Vina was used to assessing the binding affinities of the docked ligand-receptor complexes. The extract revealed the minimum inhibitory concentration value of 0.78 mg/mL. Phytol (93.58%) and 3-tetradecyn-1-ol (6.42%) were the revealed constituents. In-silico predictions suggested both compounds to have drug-like properties as they adhered to the Lipinski's rule of five. Phytol was found to have non-mutagenic effects, while 3-tetradecyn-1-ol was predicted to be mutagenic. The compounds were non-carcinogenic on mice model and carcinogenic on rat`s. Phytol has a binding affinity to DNA-gyrase and FtsZ with docking energy values of -4.1 and -5.3 kcal/mol, respectively, whereas the docking scores for 3-tetradecyn-1-ol against DNA-gyrase and FtsZ were -3.9 and -5.0 kcal/mol. The results revealed the extract to have a noteworthy activity against S. aureus, with its identified compounds having desirable pharmacokinetics. INTRODUCTION:Staphylococcus aureus is a member of the family Micrococcaceae that are characterized as catalase-positive and Grampositive aerobic cocci 1 . S. aureus is known known to cause clinical manifestations such pneumonia, endo-carditis, toxic shock syndrome, cellulitis, abscesses and impetigo at varying severity in humans 2 . Its infections are most predominant in developing countries, especially among the elderly, young children, and immunosuppressed people 3 .

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The Critical Role of Passive Permeability in Designing Successful Drugs

Cited by 65 publications

References 104 publications

Cell Permeability of Isomeric Macrocycles: Predictions and NMR Studies

Cell Permeability of Isomeric Macrocycles: Predictions and NMR Studies

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