A CoMSIA study on the adenosine kinase inhibition of pyrrolo[2,3-d]pyrimidine nucleoside analogues.

The structural requirements of pyrrolo[2,3-d]pyrimidine nucleoside (PPN) analogues as adenosine kinase (AK) inhibitors were in silico studied by using CoMSIA method. All models were trained with 32 compounds, after which they were evaluated for predictive ability with additional 5 compounds. Quantitative information on structure-activity trends is provided for further rational development and direction of selective synthesis. The best CoMSIA model included hydrophobic, H-bond donor and H-bond acceptor fields and had a good predictive quality according to internal validation criteria. In addition, this model predicted adequately the compounds contained in the test set. The analysis of the model gives a comprehensive qualitative and quantitative description of the molecular features at C4 and C5 positions of the pyrrolo[2,3-d]pyrimidine scaffold and C5-position of the beta-d-ribofuranose of PPN analogues, relevant for a high AK inhibitory activity.

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

[2]  Bruce L. Bush,et al.  Sample-distance partial least squares: PLS optimized for many variables, with application to CoMFA , 1993, J. Comput. Aided Mol. Des..

[3]  J. Devillers,et al.  Practical applications of quantitative structure-activity relationships (QSAR) in environmental chemistry and toxicology , 1990 .

[4]  Anna Artese,et al.  Rational Approaches to Anticancer Drug Design/in silico Drug Development , 2008 .

[5]  Julio Caballero,et al.  Quantitative structure-activity relationship of rubiscolin analogues as delta opioid peptides using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). , 2007, Journal of agricultural and food chemistry.

[6]  W. Gibson.  Purine and Pyrimidine Metabolism in Man VII , 1991, Advances in Experimental Medicine and Biology.

[7]  S E Ealick,et al.  Structure of human adenosine kinase at 1.5 A resolution. , 1998, Biochemistry.

[8]  R. Cramer,et al.  Validation of the general purpose tripos 5.2 force field , 1989 .

[9]  Corwin Hansch,et al.  An approach toward the problem of outliers in QSAR. , 2005, Bioorganic & medicinal chemistry.

[10]  T. Dunwiddie,et al.  Sedative and anticonvulsant effects of adenosine analogs in mouse and rat. , 1982, The Journal of pharmacology and experimental therapeutics.

[11]  S. Bhagwat.  Purinergic Approaches in Experimental Therapeutics Edited by Kenneth A. Jacobson and Michael F. Jarvis. Wiley-Liss, New York. 1997. xiv + 581 pp. 16 × 24 cm. ISBN 0-47114071-6. $89.95. , 1998 .

[12]  E. Birney,et al.  QSAR ‐ a piece of drug design , 2003, Journal of cellular and molecular medicine.

[13]  Y. Gupta,et al.  Effect of adenosine receptor modulation on pentylenetetrazole‐induced seizures in rats , 1997, British journal of pharmacology.

[14]  Maykel Pérez González,et al.  A TOPS-MODE approach to predict adenosine kinase inhibition. , 2004, Bioorganic & medicinal chemistry letters.

[15]  G. Elion,et al.  Purine and Pyrimidine Metabolism in Man VII , 1991, Advances in Experimental Medicine and Biology.

[16]  J. Daly.  Physiology and pharmacology of adenosine derivatives , 1983 .

[17]  M. Erion,et al.  Adenosine kinase inhibitors. 2. Synthesis, enzyme inhibition, and antiseizure activity of diaryltubercidin analogues. , 2000, Journal of medicinal chemistry.

[18]  Julio Caballero,et al.  2D Autocorrelation, CoMFA, and CoMSIA modeling of protein tyrosine kinases' inhibition by substituted pyrido[2,3-d]pyrimidine derivatives. , 2008, Bioorganic & medicinal chemistry.

[19]  M. Williams,et al.  Adenosine receptors: pharmacology, structure-activity relationships, and therapeutic potential. , 1992, Journal of medicinal chemistry.

[20]  J. Gasteiger,et al.  ITERATIVE PARTIAL EQUALIZATION OF ORBITAL ELECTRONEGATIVITY – A RAPID ACCESS TO ATOMIC CHARGES , 1980 .

[21]  M. Erion,et al.  Adenosine kinase inhibitors as a novel approach to anticonvulsant therapy. , 1999, The Journal of pharmacology and experimental therapeutics.

[22]  C. Hansch,et al.  p-σ-π Analysis. A Method for the Correlation of Biological Activity and Chemical Structure , 1964 .

[23]  Roberto Todeschini,et al.  Handbook of Molecular Descriptors , 2002 .

[24]  H. Haas,et al.  Inhibition of adenosine kinase increases endogenous adenosine and depresses neuronal activity in hippocampal slices , 1994, Neuropharmacology.

[25]  T. Jha,et al.  QSAR study on adenosine kinase inhibition of pyrrolo[2,3-d]pyrimidine nucleoside analogues using the hansch approach. , 2002, Bioorganic & medicinal chemistry letters.

[26]  Johann Gasteiger,et al.  Chemoinformatics: a new field with a long tradition , 2006, Analytical and bioanalytical chemistry.