Comparative Evaluation of the Predictive Power of Calculation Procedures for Molecular Lipophilicity

Mannhold, Raimund; Rekker, R. F.; Sonntag, Christoph; Laak, Antonius ter; Dross, Karl; Polymeropoulos, Emmanuel E.

doi:10.1002/jps.2600841206

Cited by 78 publications

(44 citation statements)

References 7 publications

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“…with reduced PD risk (*30%). Given the short period of treatment in many cases (*2 years), variable dosing, and low relative affinity of DHPs for Cav1.3 calcium channels (compared to Cav1.2 channels) (28,67,73), this is a surprisingly strong association and lends further credence to the proposition that a BBB permeable and potent Cav1.3 antagonist could be a very effective neuroprotective agent. That said, these studies are not a substitute for a controlled clinical trial.…”

Section: Surmeier Et Almentioning

confidence: 78%

The Origins of Oxidant Stress in Parkinson's Disease and Therapeutic Strategies

Surmeier

Guzmán

Sánchez-Padilla

et al. 2011

Antioxidants & Redox Signaling

135

109

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Parkinson's disease (PD) is a major world-wide health problem afflicting millions of the aged population. Factors that act on most or all cell types (pan-cellular factors), particularly genetic mutations and environmental toxins, have dominated public discussions of disease etiology. Although there is compelling evidence supporting an association between disease risk and these factors, the pattern of neuronal pathology and cell loss is difficult to explain without cell-specific factors. This article focuses on recent studies showing that the neurons at greatest risk in PD-substantia nigra pars compacta dopamine neurons-have a distinctive physiological phenotype that could contribute to their vulnerability. The opening of L-type calcium channels during autonomous pacemaking results in sustained calcium entry into the cytoplasm of substantia nigra pars compacta dopamine neurons, resulting in elevated mitochondrial oxidant stress and susceptibility to toxins used to create animal models of PD. This cellspecific stress could increase the negative consequences of pan-cellular factors that broadly challenge either mitochondrial or proteostatic competence. The availability of well-tolerated, orally deliverable antagonists for L-type calcium channels points to a novel neuroprotective strategy that could complement current attempts to boost mitochondrial function in the early stages of the disease.

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Section: Surmeier Et Almentioning

confidence: 78%

The Origins of Oxidant Stress in Parkinson's Disease and Therapeutic Strategies

Surmeier

Guzmán

Sánchez-Padilla

et al. 2011

Antioxidants & Redox Signaling

135

109

View full text Add to dashboard Cite

show abstract

“…The investigators agreed with the main conclusions of the Becker et al study but extended their findings by showing that only DHPs that cross the blood -brain barrier (BBB) are associated with reduced PD risk ( 30%). Given the short period of treatment in many cases ( 2 yr), variable dosing, and low relative affinity of DHPs for Ca v 1.3 Ca 2þ channels (compared to Ca v 1.2 channels (Mannhold et al 1995;Kupsch et al 1996;Eisenberg et al 2004), this is a surprisingly strong association and lends further credence to the proposition that a BBB-permeable and potent Ca v 1.3 antagonist could be a very effective neuroprotective agent. It should be noted that a small, recent study (Simon et al 2010) failed to find a significant relationship between use of Ca 2þ channel antagonists and PD risk; however, this study did not take into account the type of Ca 2þ channel antagonist used or the pharmacokinetic properties of the compounds.…”

Section: Reconciliation With Current Models Of Pd Pathogenesismentioning

confidence: 97%

Physiological Phenotype and Vulnerability in Parkinson's Disease

Surmeier

Guzmán²,

Sánchez³

et al. 2012

Cold Spring Harbor Perspectives in Medicine

102

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This review will focus on the principles underlying the hypothesis that neuronal physiological phenotype-how a neuron generates and regulates action potentials-makes a significant contribution to its vulnerability in Parkinson's disease (PD) and aging. A cornerstone of this hypothesis is that the maintenance of ionic gradients underlying excitability can pose a significant energetic burden for neurons, particularly those that have sustained residence times at depolarized membrane potentials, broad action potentials, prominent Ca 2þ entry, and modest intrinsic Ca 2þ buffering capacity. This energetic burden is shouldered in neurons primarily by mitochondria, the sites of cellular respiration. Mitochondrial respiration increases the production of damaging superoxide and other reactive oxygen species (ROS) that have widely been postulated to contribute to cellular aging and PD. Many of the genetic mutations and toxins associated with PD compromise mitochondrial function, providing a mechanistic linkage between known risk factors and cellular physiology that could explain the pattern of pathology in PD. Because much of the mitochondrial burden created by this atrisk phenotype is created by Ca 2þ entry through L-type voltage-dependent channels for which there are antagonists approved for human use, a neuroprotective strategy to reduce this burden is feasible.

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“…The corresponding correction in the predicted log P (0.72) is quite close to that measured between, for example, o-versus m-hydroxybenzoic acid (2.24 Ϫ 1.49 ϭ 0.75) or even to that used in different fragmental methods to account for intramolecular H bonding: 0.63 in CLOGP, 1 0.66 in Rekker's revised method. 46 Two reasonable modifications had to be made. For structures containing side chains with aliphatic -OH groups (Ser, Thr) log P was consistently underestimated with about 0.5-0.7 units.…”

Section: Modelmentioning

confidence: 99%

Octanol–water partition of nonzwitterionic peptides: Predictive power of a molecular size-based model

Buchwald

Bodor

1998

Proteins

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A remarkably simple, molecular size-based model developed to predict octanol-water partition coefficients for organic compounds is tested on a set of 188 neutral peptides with available experimental partition data. Despite using only two parameters, it gives a promising correlation (r2 = 0.914; sigma = 0.455, F = 1978.0), and predictions are in a realistic range even for larger peptides (cyclosporin, melanotan, sandostatin) where common, overparametrized fragment methods become quite unreliable. Ion-pair partitioning and the extraction constant formalism is briefly reviewed to describe the sigmoidal lipophilicity profile of ionizable, nonzwitterionic peptides. It seems possible to extend the present model to estimate apparent partition coefficients measured around neutral pH and physiological conditions for monoionic peptides; however, as no standard conditions are yet defined and only relatively small number of experimental data are available, the situation here is more complex.

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Comparative Evaluation of the Predictive Power of Calculation Procedures for Molecular Lipophilicity

Cited by 78 publications

References 7 publications

The Origins of Oxidant Stress in Parkinson's Disease and Therapeutic Strategies

The Origins of Oxidant Stress in Parkinson's Disease and Therapeutic Strategies

Physiological Phenotype and Vulnerability in Parkinson's Disease

Octanol–water partition of nonzwitterionic peptides: Predictive power of a molecular size-based model

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