Rudy J Richardson

Publications (96) View all

• Source

  Available from: Galina Makhaeva

  Dataset: Makhaeva 2012 SARQSAR

  G F Makhaeva, E V Radchenko, I I Baskin, V A Palyulin, R J Richardson, N S Zefirov
• Source

  Available from: Igor I. Baskin

  Article: Combined QSAR studies of inhibitor properties of O-phosphorylated oximes toward serine esterases involved in neurotoxicity, drug metabolism and Alzheimer's disease.

  G F Makhaeva, E V Radchenko, I I Baskin, V A Palyulin, R J Richardson, N S Zefirov
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  ABSTRACT: Oxime reactivation of serine esterases (EOHs) inhibited by organophosphorus (OP) compounds can produce O-phosphorylated oximes (POXs). Such oxime derivatives are of interest, because some of them can have greater anti-EOH potencies than the OP inhibitors from which they were derived. Accordingly, inhibitor properties of 58 POXs against four EOHs, along with pair-wise selectivities between them, have been analysed using different QSAR approaches. EOHs (with their abbreviations and consequences of inhibition in parentheses) comprised acetylcholinesterase (AChE: acute neurotoxicity; cognition enhancement), butyrylcholinesterase (BChE: inhibition of drug metabolism or stoichiometric scavenging of EOH inhibitors; cognition enhancement), carboxylesterase (CaE: inhibition of drug metabolism or stoichiometric scavenging of EOH inhibitors), and neuropathy target esterase (NTE: delayed neurotoxicity). QSAR techniques encompassed linear regression and backpropagation neural networks in conjunction with fragmental descriptors containing labelled atoms, Molecular Field Topology Analysis (MFTA), Comparative Molecular Similarity Index Analysis (CoMSIA), and molecular modelling. All methods provided mostly consistent and complementary information, and they revealed structural features controlling the 'esterase profiles', i.e. patterns of anti-EOH activities and selectivities of the compounds of interest. In addition, MFTA models were used to design a library of compounds having a cognition-enhancement esterase profile suitable for potential application to the treatment of Alzheimer's disease.
  SAR and QSAR in environmental research 05/2012; 23(7-8):627-647. · 1.68 Impact Factor
• Source

  Available from: Galina Makhaeva

  Article: Kinetics and mechanism of inhibition of serine esterases by fluorinated aminophosphonates.

  G F Makhaeva, A Y Aksinenko, V B Sokolov, I I Baskin, V A Palyulin, N S Zefirov, N D Hein, J W Kampf, S J Wijeyesakere, R J Richardson
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  ABSTRACT: This paper reviews previously published data and presents new results to address the hypothesis that fluorinated aminophosphonates (FAPs), (RO)(2)P(O)C(CF(3))(2)NHS(O)(2)C(6)H(5), R=alkyl, inhibit serine esterases by scission of the P-C bond. Kinetics studies demonstrated that FAPs are progressive irreversible inhibitors of acetylcholinesterase (AChE, EC 3.1.1.7.), butyrylcholinesterase (BChE, EC 3.1.1.8.), carboxylesterase (CaE, EC 3.1.1.1.), and neuropathy target esterase (NTE, EC 3.1.1.5.), consistent with P-C bond breakage. Chemical reactivity experiments showed that diMe-FAP and diEt-FAP react with water to yield the corresponding dialkylphosphates and (CF(3))(2)CHNHS(O)(2)C(6)H(5), indicating lability of the P-C bond. X-ray crystallography of diEt-FAP revealed an elongated (and therefore weaker) P-C bond (1.8797 (13)A) compared to P-C bonds in dialkylphosphonates lacking alpha-CF(3) groups (1.805-1.822A). Semi-empirical and non-empirical molecular modeling of diEt-FAP and (EtO)(2)P(O)C(CH(3))(2)NHS(O)(2)C(6)H(5) (diEt-AP), which lacks CF(3) groups, indicated lengthening and destabilization of the P-C bond in diEt-FAP compared to diEt-AP. Active site peptide adducts formed by reacting diEt-FAP with BChE and diBu-FAP with NTE catalytic domain (NEST) were identified using peptide mass mapping with mass spectrometry (MS). Mass shifts (mean+/-SE, average mass) for peaks corresponding to active site peptides with diethylphosphoryl and monoethylphosphoryl adducts on BChE were 136.1+/-0.1 and 108.0+/-0.1Da, respectively. Corresponding mass shifts for dibutylphosphoryl and monobutylphosphoryl adducts on NEST were 191.8+/-0.2 and 135.5+/-0.1Da, respectively. Each of these values was statistically identical to the theoretical mass shift for each dialkylphosphoryl and monoalkylphosphoryl species. The MS results demonstrate that inhibition of BChE and NEST by FAPs yields dialkylphosphoryl and monoalkylphosphoryl adducts, consistent with phosphorylation via P-C bond cleavage and aging by net dealkylation. Taken together, predictions from enzyme kinetics, chemical reactivity, X-ray crystallography, and molecular modeling were confirmed by MS and support the hypothesis that FAPs inhibit serine esterases via scission of the P-C bond.
  Chemico-biological interactions 09/2010; 187(1-3):177-84. · 2.46 Impact Factor
• Article: Chlorpyrifos exposure and biological monitoring among manufacturing workers.

  C J Burns, D Garabrant, J W Albers, S Berent, B Giordani, S Haidar, R Garrison, R J Richardson
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  ABSTRACT: To use biological monitoring data to evaluate the soundness of job based exposure classifications. The authors studied 52 chlorpyrifos manufacturing workers and 60 referent workers to compare chlorpyrifos exposure estimations from job titles and work areas to urinary excretion of 3,5,6 trichloro-2-pyridinol (TCP), a metabolite of chlorpyrifos. Work history records and industrial hygiene monitoring data were used to establish cumulative interim exposure. Chlorpyrifos exposure during the study year was assessed biologically by urinary excretion of TCP. Exposure as measured by three urinary TCP samples was significantly higher among the chlorpyrifos workers (188 microg/l) than it was for the referent subjects (7 microg/l). Urinary TCP also correlated well with specific exposure categories of negligible (0.73-1.98 mg/m3 days), low (1.99-4.91 mg/m3 days), and moderate (4.92-15.36 mg/m3 days). The weighted Kappa coefficient was 0.80 (95% CI 0.72 to 0.87) for the mean TCP over the study period. The estimates of chlorpyrifos exposure based on job classifications and industrial hygiene measurements were significantly related to urinary TCP excretion, indicating that the ambient estimates are useful for providing exposure estimates among chlorpyrifos manufacturing workers.
  Occupational and environmental medicine 04/2006; 63(3):218-20. · 3.64 Impact Factor
• Article: Improved Electrochemical Analysis of Neuropathy Target Esterase Activity by a Tyrosinase Carbon Paste Electrode Modified by 1-Methoxyphenazine Methosulfate

  L.G. Sokolovskaya, L.V. Sigolaeva, A.V. Eremenko, I.V. Gachok, G.F. Makhaeva, N.N. Strakhova, V.V. Malygin, R.J. Richardson, I.N. Kurochkin
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  ABSTRACT: A graphite-paste tyrosinase biosensor was improved by adding 1-methoxyphenazine methosulfate as a mediator. Mediator modification enhanced sensitivity to phenol 4-fold and long-term stability 3-fold. Phenol could be detected at 25nM (S/N=2) using an Ag/AgCl reference electrode. The biosensor was used to measure the activity of a toxicologically significant enzyme, neuropathy target esterase (NTE), which yields phenol by hydrolysis of the substrate, phenyl valerate. Using the new biosensor, blood and brain NTE inhibition by organophosphorus (OP) compounds with different neuropathic potencies were well correlated (r=0.990, n=7), supporting the use of blood NTE as a biochemical marker of exposure to neuropathic OP compounds.
  Biotechnology Letters 07/2005; 27(16):1211-1218. · 1.68 Impact Factor