Modeling the LPS Neutralization Activity of Anti-Endotoxins

Bacterial lipopolysaccharides (LPS), also known as endotoxins, are major structural components of the outer membrane of Gram-negative bacteria that serve as a barrier and protective shield between them and their surrounding environment. LPS is considered to be a major virulence factor as it strongly stimulates the secretion of pro-inflammatory cytokines which mediate the host immune response and culminating in septic shock. Quantitative structure-activity relationship studies of the LPS neutralization activities of anti-endotoxins were performed using charge and quantum chemical descriptors. Artificial neural network implementing the back-propagation algorithm was selected for the multivariate analysis. The predicted activities from leave-one-out cross-validation were well correlated with the experimental values as observed from the correlation coefficient and root mean square error of 0.930 and 0.162, respectively. Similarly, the external testing set also yielded good predictivity with correlation coefficient and root mean square error of 0.983 and 0.130. The model holds great potential for the rational design of novel and robust compounds with enhanced neutralization activity.

[1]  Apilak Worachartcheewan,et al.  Modeling the activity of furin inhibitors using artificial neural network. , 2009, European journal of medicinal chemistry.

[2]  C. Nantasenamat,et al.  Prediction of bond dissociation enthalpy of antioxidant phenols by support vector machine. , 2008, Journal of molecular graphics & modelling.

[3]  Chartchalerm Isarankura-Na-Ayudhya,et al.  QSAR model of the quorum-quenching N-acyl-homoserine lactone lactonase activity , 2008 .

[4]  Chartchalerm Isarankura-Na-Ayudhya,et al.  Quantitative structure-imprinting factor relationship of molecularly imprinted polymers. , 2007, Biosensors & bioelectronics.

[5]  Chartchalerm Isarankura-Na-Ayudhya,et al.  Prediction of GFP spectral properties using artificial neural network , 2007, J. Comput. Chem..

[6]  G. Georg,et al.  Novel endotoxin-sequestering compounds with terephthalaldehyde-bis-guanylhydrazone scaffolds. , 2006, Bioorganic & medicinal chemistry letters.

[7]  R. Munford.  Severe sepsis and septic shock: the role of gram-negative bacteremia. , 2006, Annual review of pathology.

[8]  K. Miller,et al.  Structure-activity relationships in lipopolysaccharide neutralizers: design, synthesis, and biological evaluation of a 540-membered amphipathic bisamide library. , 2006, Journal of combinatorial chemistry.

[9]  Jaroslaw Polanski,et al.  A 4D-QSAR study on anti-HIV HEPT analogues. , 2006, Bioorganic & medicinal chemistry.

[10]  Ashutosh,et al.  Comment to: septic shock: current pathogenic concept from a clinical perspective Tsiotou AG, Sakorafas GH, Anagnostopoulos G, Bramis J Med Sci Monit, 2005; 11(3): RA76-RA85 Future treatment perspectives in septic shock. , 2005, Medical science monitor : international medical journal of experimental and clinical research.

[11]  Virapong Prachayasittikul,et al.  Quantitative prediction of imprinting factor of molecularly imprinted polymers by artificial neural network , 2005, J. Comput. Aided Mol. Des..

[12]  Chartchalerm Isarankura-Na-Ayudhya,et al.  Recognition of DNA Splice Junction via Machine Learning Approaches , 2005 .

[13]  Darren H. Wakefield,et al.  Membrane activity and transfection ability of amphipathic polycations as a function of alkyl group size. , 2005, Bioconjugate chemistry.

[14]  K. Miller,et al.  Lipopolysaccharide sequestrants: structural correlates of activity and toxicity in novel acylhomospermines. , 2005, Journal of medicinal chemistry.

[15]  T. Nguyen,et al.  Lysine-spermine conjugates: hydrophobic polyamine amides as potent lipopolysaccharide sequestrants. , 2005, Bioorganic & medicinal chemistry.

[16]  G. Sakorafas,et al.  Septic shock; current pathogenetic concepts from a clinical perspective. , 2005, Medical science monitor : international medical journal of experimental and clinical research.

[17]  B. Ho,et al.  De Novo Design of Potent Antimicrobial Peptides , 2004, Antimicrobial Agents and Chemotherapy.

[18]  G. Martin,et al.  A global perspective on the epidemiology of sepsis , 2004, Intensive Care Medicine.

[19]  James J. Filliben,et al.  NIST/SEMATECH e-Handbook of Statistical Methods; Chapter 1: Exploratory Data Analysis , 2003 .

[20]  D. Mannino,et al.  The epidemiology of sepsis in the United States from 1979 through 2000. , 2003, The New England journal of medicine.

[21]  Ş. Niculescu.  Artificial neural networks and genetic algorithms in QSAR , 2003 .

[22]  A J Hopfinger,et al.  4D-QSAR analysis of a set of propofol analogues: mapping binding sites for an anesthetic phenol on the GABA(A) receptor. , 2002, Journal of medicinal chemistry.

[23]  Ian H. Witten,et al.  Data mining: practical machine learning tools and techniques with Java implementations , 2002, SGMD.

[24]  C. Whitfield,et al.  Lipopolysaccharide endotoxins. , 2002, Annual review of biochemistry.

[25]  S. David.  Towards a rational development of anti‐endotoxin agents: novel approaches to sequestration of bacterial endotoxins with small molecules , 2001, Journal of molecular recognition : JMR.

[26]  W. DeGrado,et al.  De Novo Design, Synthesis, and Characterization of Antimicrobial β-Peptides , 2001 .

[27]  J. Tam,et al.  Design of Gram-negative selective antimicrobial peptides. , 2001, Biochemistry.

[28]  Y. L. Loukas,et al.  Artificial neural networks in liquid chromatography: efficient and improved quantitative structure-retention relationship models. , 2000, Journal of chromatography. A.

[29]  Rafael Gozalbes,et al.  Prediction of Quinolone Activity against Mycobacterium avium by Molecular Topology and Virtual Computational Screening , 2000, Antimicrobial Agents and Chemotherapy.

[30]  Martyn G. Ford,et al.  Unsupervised Forward Selection: A Method for Eliminating Redundant Variables , 2000, J. Chem. Inf. Comput. Sci..

[31]  S. Agatonovic-Kustrin,et al.  Use of ANN modelling in structure--retention relationships of diuretics in RP-HPLC. , 1999, Journal of pharmaceutical and biomedical analysis.

[32]  C. Amura,et al.  Lipopolyamines: Novel Antiendotoxin Compounds That Reduce Mortality in Experimental Sepsis Caused by Gram-Negative Bacteria , 1999, Antimicrobial Agents and Chemotherapy.

[33]  M. Rothe,et al.  Bacterial Lipopolysaccharide Activates Nuclear Factor-κB through Interleukin-1 Signaling Mediators in Cultured Human Dermal Endothelial Cells and Mononuclear Phagocytes* , 1999, The Journal of Biological Chemistry.

[34]  R. Ulevitch,et al.  Recognition of gram-negative bacteria and endotoxin by the innate immune system. , 1999, Current opinion in immunology.

[35]  Han Liu,et al.  Application of artificial neural networks for prediction of the retention indices of alkylbenzenes , 1999 .

[36]  Johann Gasteiger,et al.  Neural networks in chemistry and drug design , 1999 .

[37]  A. Cross,et al.  ANTIENDOTOXIN ANTIBODIES. AUTHOR'S REPLY , 1995 .

[38]  J. Siegel.  Antiendotoxin antibodies. , 1995, Annals of internal medicine.

[39]  H. Masoud,et al.  General strategy for structural analysis of the oligosaccharide region of lipooligosaccharides. Structure of the oligosaccharide component of Pseudomonas aeruginosa IATS serotype 06 mutant R5 rough-type lipopolysaccharide. , 1994, Biochemistry.

[40]  B. Lindner,et al.  Molecular structure of lipid A, the endotoxic center of bacterial lipopolysaccharides. , 1994, Advances in carbohydrate chemistry and biochemistry.

[41]  J. Hurley,et al.  Antibiotic-induced release of endotoxin: a reappraisal. , 1992, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[42]  M. Vaara,et al.  Effective Inhibition of Cardiolipin‐Binding Antibodies in Gram‐Negative Infections by Bacterial Lipopolysaccharide , 1988, Scandinavian journal of immunology.

[43]  A. Cross,et al.  Functional activities of monoclonal antibodies to the O side chain of Escherichia coli lipopolysaccharides in vitro and in vivo. , 1988, The Journal of infectious diseases.

[44]  E. Rietschel,et al.  Isolation and analysis of the lipid A backbone. Lipid A structure of lipopolysaccharides from various bacterial groups. , 1976, European journal of biochemistry.