TOPS-MODE Based QSARs Derived from Heterogeneous Series of Compounds. Applications to the Design of New Herbicides

A new application of TOPological Sub-structural MOlecular DEsign (TOPS-MODE) was carried out in herbicides using computer-aided molecular design. Two series of compounds, one containing herbicide and the other containing nonherbicide 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 herbicides from the nonherbicide compounds was developed. The model correctly and clearly classified 88% of active and 94% of inactive compounds in the training set. More specifically, the model showed a good global classification of 91%, i.e., (168 cases out of 185). While in the prediction set, they showed an overall predictability of 91% and 92% for active and inactive compounds, being the global percentage of good classification of 92%. To assess the range of model applicability, a virtual screening of structurally heterogeneous series of herbicidal compounds was carried out. Two hundred eighty-four out of 332 were correctly classified (86%). Furthermore this paper describes a fragment analysis in order to determine the contribution of several fragments toward herbicidal 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 herbicides discovery.

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

[2]  Henk J. M. Verhaar,et al.  QSAR modelling of soil sorption. Improvements and systematics of log KOC vs. log KOW correlations , 1995 .

[3]  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..

[4]  D. Shaner,et al.  Modeling root absorption and translocation of 5‐substituted analogs of the imidazolinone herbicide, imazapyr , 1994 .

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

[6]  J. Mihelcic,et al.  Reliable QSAR for estimating Koc for persistent organic pollutants: correlation with molecular connectivity indices. , 2001, Chemosphere.

[7]  P. Gramatica,et al.  Modelling and prediction of soil sorption coefficients of non-ionic organic pesticides by molecular descriptors. , 2000, Chemosphere.

[8]  Ernesto Estrada,et al.  Modeling Diamagnetic and Magnetooptic Properties of Organic Compounds with the TOSS-MODE Approach , 2000, J. Chem. Inf. Comput. Sci..

[9]  Jon A. Erickson,et al.  A comparative molecular field analysis study of obtusifoliol 14α-methyl demethylase inhibitors † , 1999 .

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

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

[12]  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..

[13]  Humberto González Díaz,et al.  Markovian chemicals "in silico" design (MARCH-INSIDE), a promising approach for computer aided molecular design II: experimental and theoretical assessment of a novel method for virtual screening of fasciolicides , 2002, Journal of molecular modeling.

[14]  R. García-Domenech,et al.  Antimicrobial Activity Characterization in a Heterogeneous Group of Compounds. , 1998 .

[15]  Ernesto Estrada.  Generalized Spectral Moments of the Iterated Line Graphs Sequence. A Novel Approach to QSPR Studies , 1999, J. Chem. Inf. Comput. Sci..

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

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

[18]  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..

[19]  J. Huppatz.  Quantifying the Inhibitor-Target Site Interactions of Photosystem II Herbicides , 1996, Weed Science.

[20]  Milan Randic,et al.  Orthogonal molecular descriptors , 1991 .

[21]  Milan Randić,et al.  Correlation of enthalphy of octanes with orthogonal connectivity indices , 1991 .

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

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

[24]  M. A. Cabrera Pérez,et al.  A novel approach to determining physicochemical and absorption properties of 6-fluoroquinolone derivatives: experimental assessment. , 2002, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[25]  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.

[26]  Ernesto Estrada,et al.  Combination of 2D-, 3D-Connectivity and Quantum Chemical Descriptors in QSPR. Complexation of - and -Cyclodextrin with Benzene Derivatives , 2001, J. Chem. Inf. Comput. Sci..

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

[28]  E Estrada,et al.  In silico studies for the rational discovery of anticonvulsant compounds. , 2000, Bioorganic & medicinal chemistry.

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

[30]  K. N. Reddy,et al.  Prediction of Soil Sorption (Koc) of Herbicides Using Semiempirical Molecular Properties , 1994, Weed Science.

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

[32]  H. Kubinyi,et al.  A scoring scheme for discriminating between drugs and nondrugs. , 1998, Journal of medicinal chemistry.

[33]  Milan Randic,et al.  Resolution of ambiguities in structure-property studies by use of orthogonal descriptors , 1991, J. Chem. Inf. Comput. Sci..

[34]  R. Clark.  Synthesis and QSAR of Herbicidal 3-Pyrazolyl α,α,α-Trifluorotolyl Ethers , 1996 .

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

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

[37]  James W. McFarland,et al.  Cluster Significance Analysis: A New Qsar Tool for Asymmetric Data Sets , 1990 .