Musings on ADME Predictions and Structure-Activity Relations

Testa, Bernard; Vistoli, Giulio; Pedretti, Alessandro

doi:10.1002/cbdv.200590115

Cited by 21 publications

(9 citation statements)

References 16 publications

(13 reference statements)

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“…Conclusions. -As we have argued elsewhere, significant molecular information is neglected in the descriptors used in QSAR investigations [12] [22]. A missing dimension when encoding chemical information is certainly the dynamic nature of molecules.…”

Section: Influence Of Ionization On Lipophilicity Spacementioning

confidence: 97%

Partition Coefficient and Molecular Flexibility: The Concept of Lipophilicity Space

Vistoli

Pedretti

Testa

2009

Chemistry & Biodiversity

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The rationale of this study was to investigate molecular flexibility and its influence on physicochemical properties with a view to uncovering additional information on the fuzzy concept of dynamic molecular structure. Indeed, it is now known that computed molecular interaction fields (MIFs) such as molecular electrostatic potentials (MEPs) and lipophilicity potentials (MLPs) are conformation-dependent, as are dipole moments. A database of 125 compounds was used whose conformational space was explored, while conformation-dependent parameters were computed for each non-redundant conformer found in the conformational space of the compounds. These parameters were the virtual log P (log P(MLP), calculated by a MLP approach), the apolar surface area (ASA), polar surface area (PSA), and solvent-accessible surface (SAS). For each compound, the range taken by each parameter (its property space) was divided by the number of rotors taken as an index of flexibility, yielding a parameter termed 'molecular sensitivity'. This parameter was poorly correlated with others (i.e., it contains novel information) and showed the compounds to fall into two broad classes. 'Sensitive' molecules are those whose computed property ranges are markedly sensitive to conformational effects, whereas 'insensitive' (in fact, less sensitive) molecules have property ranges which are comparatively less affected by conformational fluctuations. A pharmacokinetic application is presented.

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Section: Influence Of Ionization On Lipophilicity Spacementioning

confidence: 97%

Partition Coefficient and Molecular Flexibility: The Concept of Lipophilicity Space

Vistoli

Pedretti

Testa

2009

Chemistry & Biodiversity

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“…Basically, there are two types of interactions between bioactive compounds and biological systems [6,11]. A drug acting on a biological system elicits a pharmacological and/or a toxic response, in other words a pharmacodynamic (PD) event.…”

Section: The Pk-pd Interplaymentioning

confidence: 99%

“…11 A schematic comparison of the mechanism of activation of the anti-aggregating bioprecursors clopidogrel(28) and prasugrel(32) to their (re)active sulfenic acid metabolite 31 and 35, respectively. The lower part of the figure shows a mechanism of glutathione-mediated reduction of the sulfenic acid to the corresponding thiol, which was believed for years to be the active metabolite.…”

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confidence: 99%

Role of PhaseIMetabolism in Drug Activation and Clinical Treatment Outcomes

Testa

Pannatier

2012

Encyclopedia of Drug Metabolism and Interactions

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This chapter explores the relation between drug biotransformation and pharmacological activity. More precisely, it surveys the formation of active metabolites and exemplifies cases of metabolites as or more active than the parent drug. Because very few drug conjugates are pharmacologically active, the focus is on metabolic reactions of functionalization (i.e., phase I), namely, oxidations, reductions, or hydrolyses.The first section sets the scene by explaining the pharmacokinetic/pharmacodynamic (PK/PD) interplay that underlies drug action, and the existing continuum ranging from drugs devoid of active metabolites, to drugs yielding some active metabolite(s), to prodrugs whose activity is due solely to the metabolite. Soft drugs are briefly exemplified since they nicely illustrate the concept of drugs designed to be rapidly metabolized to inactive, atoxic metabolites.

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“…Pharmacokinetic is often studied in conjunction with pharmacodynamics. Pharmacodynamics explores what a drug does to the body, whereas pharmacokinetics explores what the biological system does to the drug [79]. Pharmacokinetics includes the study of the mechanisms of absorption and distribution of an administered drug, the rate at which a drug action begins and the duration of the effect, the chemical changes of the substance in the body (e.g., by enzymes), and the effects and routes of excretion (of the metabolites) of the drug.…”

Section: Definitionsmentioning

confidence: 99%