TOPS-MODE based QSARs derived from heterogeneous series of compounds. Applications to the design of new anti-inflammatory compounds.

A new application of TOPological Sub-structural MOlecular DEsign (TOPS-MODE) was carried out in anti-inflammatory compounds using computer-aided molecular design. Two series of compounds, one containing anti-inflammatory and the other containing nonanti-inflammatory compounds were processed by a k-means cluster analysis in order to design the training and prediction sets. A linear classification function to discriminate the anti-inflammatory from the inactive compounds was developed. The model correctly and clearly classified 88% of active and 91% of inactive compounds in the training set. More specifically, the model showed a good global classification of 90%, that is, (399 cases out of 441). While in the prediction set, they showed an overall predictability of 88% and 84% for active and inactive compounds, being the global percentage of good classification of 85%. Furthermore this paper describes a fragment analysis in order to determine the contribution of several fragments towards anti-inflammatory property, also the present of halogens in the selected fragments were analyzed. It seems that the present TOPS-MODE based QSAR is the first alternate general 'in silico' technique to experimentation in anti-inflammatory discovery.

[1]  Humberto González Díaz,et al.  Modeling Diamagnetic and Magnetooptic Properties of Organic Compounds with the TOSS-MODE Approach , 2000, J. Chem. Inf. Comput. Sci..

[2]  F. Menestrina,et al.  Anti-inflammatory potency and gastrointestinal toxicity of a new compound, nitronaproxen. , 1995, Pharmacological research.

[3]  Ernesto Estrada,et al.  QSPR/QSAR by Graph Theoretical Descriptors Beyond the Frontiers , 2001 .

[4]  Humberto González Díaz,et al.  What Are the Limits of Applicability for Graph Theoretic Descriptors in QSPR/QSAR? Modeling Dipole Moments of Aromatic Compounds with TOPS-MODE Descriptors , 2003, J. Chem. Inf. Comput. Sci..

[5]  Ernesto Estrada,et al.  Spectral Moments of the Edge Adjacency Matrix in Molecular Graphs. 3. Molecules Containing Cycles , 1998, J. Chem. Inf. Comput. Sci..

[6]  Philippe Chavatte,et al.  Investigations of new lead structures for the design of novel cyclooxygenase-2 inhibitors. , 2002, European journal of medicinal chemistry.

[7]  C. Torrance,et al.  Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs. , 1992, The New England journal of medicine.

[8]  Bruce R. Kowalski,et al.  31 Pattern recognition in chemistry , 1982, Classification, Pattern Recognition and Reduction of Dimensionality.

[9]  H. Díaz,et al.  A TOPS-MODE approach to predict permeability coefficients , 2004 .

[10]  E Uriarte,et al.  Quantitative Structure–Toxicity Relationships Using Tops-Mode. 1. Nitrobenzene Toxicity to Tetrahymena Pyriformis , 2001, SAR and QSAR in environmental research.

[11]  Rainer Franke,et al.  Theoretical drug design methods , 1984 .

[12]  R. Ottanà,et al.  Aminopyrazinyl derivatives: synthesis and evaluation of antiinflammatory and related activities. , 1994, Farmaco.

[13]  K. Seibert,et al.  The induction and suppression of prostaglandin H2 synthase (cyclooxygenase) in human monocytes. , 1990, The Journal of biological chemistry.

[14]  Ernesto Estrada,et al.  A novel approach for the virtual screening and rational design of anticancer compounds. , 2000, Journal of medicinal chemistry.

[15]  Hiromasa Hashimoto,et al.  4-Aryl/cycloalkyl-5-phenyloxazole derivatives as selective COX-2 inhibitors. , 2002, Bioorganic & medicinal chemistry letters.

[16]  P. Worley,et al.  COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[17]  P. Delmas.  Non-steroidal anti-inflammatory drugs and renal function. , 1995, British journal of rheumatology.

[18]  J. Vane,et al.  Activity of Various Fractions of Bradykinin Potentiating Factor against Angiotensin I Converting Enzyme , 1970, Nature.

[19]  J. Vane,et al.  Mechanism of action of anti-inflammatory drugs. , 1997, Advances in experimental medicine and biology.

[20]  William L Jorgensen,et al.  Estimation of binding affinities for celecoxib analogues with COX-2 via Monte Carlo-extended linear response. , 2002, Bioorganic & medicinal chemistry letters.

[21]  E Uriarte,et al.  Recent advances on the role of topological indices in drug discovery research. , 2001, Current medicinal chemistry.

[22]  Milan Randic,et al.  Fitting of nonlinear regressions by orthogonalized power series , 1993, J. Comput. Chem..

[23]  S. Balaz,et al.  Structure-mutagenicity relationships of 5-nitro-2-furylethylenes in Salmonella typhimurium TA98. , 1985, Chemico-biological interactions.

[24]  H. Jacobson,et al.  Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. , 1994, The Journal of clinical investigation.

[25]  M. Murray,et al.  Renal toxicity of the nonsteroidal anti-inflammatory drugs. , 1993, Annual review of pharmacology and toxicology.

[26]  M. Goppelt‐Struebe,et al.  Up‐regulation of cyclooxygenase‐2 mRNA in the rat spinal cord following peripheral inflammation , 1996, FEBS letters.

[27]  R. D. Dyer,et al.  Synthesis and biological evaluation of 5-[[3,5-bis(1,1-dimethylethyl)- 4-hydroxyphenyl]methylene]oxazoles, -thiazoles, and -imidazoles: novel dual 5-lipoxygenase and cyclooxygenase inhibitors with antiinflammatory activity. , 1994, Journal of medicinal chemistry.

[28]  S. Balaz,et al.  Relationships between structure of 5-nitro-2-furylethylenes and their SOS-function-inducing activities in Escherichia coli. , 1986, Chemico-biological interactions.

[29]  Ramón García-Domenech,et al.  Designing sedative/hypnotic compounds from a novel substructural graph-theoretical approach , 1998, Journal of computer-aided molecular design.

[30]  E Uriarte,et al.  Quantitative structure-toxicity relationships using TOPS-MODE. 3. Structural factors influencing the permeability of commercial solvents through living human skin , 2003, SAR and QSAR in environmental research.

[31]  Miguel A. Cabrera,et al.  TOPS-MODE approach for the prediction of blood-brain barrier permeation. , 2004, Journal of pharmaceutical sciences.

[32]  Ernesto Estrada,et al.  Spectral Moments of the Edge Adjacency Matrix in Molecular Graphs, 1. Definition and Applications to the Prediction of Physical Properties of Alkanes , 1996, J. Chem. Inf. Comput. Sci..

[33]  William L. Smith,et al.  Prostaglandin Endoperoxide H Synthases (Cyclooxygenases)-1 and −2* , 1996, The Journal of Biological Chemistry.

[34]  M. Demeo.  Sucrose permeability as a marker for nonsteroidal anti-inflammatory gastroduodenal injury: how sweet is it? , 2009, Nutrition reviews.

[35]  K. Schrör,et al.  Constitutive cyclooxygenase-2 expression in healthy human and rabbit gastric mucosa. , 1998, Molecular pharmacology.

[36]  M Grubb,et al.  Antiinflammatory 4,5-diarylpyrroles: synthesis and QSAR. , 1994, Journal of medicinal chemistry.

[37]  Ernesto Estrada,et al.  Edge Adjacency Relationships and a Novel Topological Index Related to Molecular Volume , 1995, J. Chem. Inf. Comput. Sci..

[38]  Lawrence J Marnett,et al.  Amide derivatives of meclofenamic acid as selective cyclooxygenase-2 inhibitors. , 2002, Bioorganic & medicinal chemistry letters.

[39]  E. Knaus,et al.  Synthesis and antiinflammatory activity of 5-(1,6-dihydropyridyl)-tetrazol-2-acetic acids, esters and amides. , 1994, Drug design and discovery.

[40]  Maykel Pérez González,et al.  TOPS-MODE Based QSARs Derived from Heterogeneous Series of Compounds. Applications to the Design of New Herbicides , 2003, J. Chem. Inf. Comput. Sci..

[41]  Ernesto Estrada,et al.  Spectral Moments of the Edge-Adjacency Matrix of Molecular Graphs, 2. Molecules Containing Heteroatoms and QSAR Applications , 1997, J. Chem. Inf. Comput. Sci..

[42]  Ernesto Estrada,et al.  Modelling the diamagnetic susceptibility of organic compounds by a sub-structural graph-theoretical approach , 1998 .

[43]  Richard A. Johnson,et al.  Applied Multivariate Statistical Analysis , 1983 .

[44]  H. Kubinyi.  QSAR : Hansch analysis and related approaches , 1993 .

[45]  Kazuo Nagasawa,et al.  Thalidomide and its analogues as cyclooxygenase inhibitors. , 2002, Bioorganic & medicinal chemistry letters.

[46]  Jesús Vicente de Julián-Ortiz,et al.  Topological Approach to Drug Design , 1995, J. Chem. Inf. Comput. Sci..

[47]  C. Hawkey,et al.  Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiinflammatory drugs. , 1996, The New England journal of medicine.

[48]  R. Pouplana,et al.  Structure-based QSAR study on differential inhibition of human prostaglandin endoperoxide H synthase-2 (COX-2) by nonsteroidal anti-inflammatory drugs , 2002, J. Comput. Aided Mol. Des..

[49]  J. Sibley,et al.  An evidence-based approach to prescribing NSAIDs in musculoskeletal disease: a Canadian consensus. Canadian NSAID Consensus Participants. , 1996, CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne.

[50]  Kurt Varmuza,et al.  Pattern recognition in chemistry , 1980 .

[51]  R. García Doménech,et al.  Prediction and Interpretation of Some Pharmacological Properties of Cephalosporins Using Molecular Connectivity , 1991 .

[52]  E Estrada,et al.  Modeling chromatographic parameters by a novel graph theoretical sub-structural approach. , 1999, Journal of chromatography. A.