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Homology models of the catalytic sites of phosphodiesterase 5A and 10A and molecular docking of selective apoptotic antineoplastic drugs (SAANDs)
Author(s) -
Salter E. A.,
Wierzbicki A.,
Sperl G.,
Thompson W. J.
Publication year - 2003
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.10733
Subject(s) - phosphodiesterase , docking (animal) , chemistry , isozyme , homology modeling , gene isoform , molecular mechanics , stereochemistry , active site , apoptosis , molecular model , biochemistry , enzyme , gene , microbiology and biotechnology , biophysics , computational biology , molecular dynamics , biology , medicine , computational chemistry , nursing
Achieving selective inhibition for individual gene families of cyclic nucleotide phosphodiesterases (CNPDE) isoenzymes has become an important pharmacological goal now that the diversity of these hydrolases has been recognized. Selective apoptotic antineoplastic drugs (SAANDs) induce apoptosis in neoplastic cells and not in normal cells by a mechanism involving inhibition of overexpressed PDEs that hydrolyze cyclic GMP. SAANDs, although not selective, show a preference for PDE5 and PDE10. However, highly selective PDE5 inhibitors do not induce apoptosis. To study differences in PDE inhibitors, we constructed homology models of the target catalytic domains of PDE5A and PDE10A based upon the X‐ray crystal structure of the catalytic domain of PDE4B. Molecular mechanics docking is planned to define new SAANDs vs. ineffective agents. We investigated the binding of exisulind (Aptosyn and other analogs to PDE4, 5, and 10 isoforms using our molecular models and compared the resultant estimated binding energies with experimental IC 50 values. Proposed binding orientations for CP 248, a higher‐affinity and more selective inhibitor of PDE5 and PDE10 than exisulind, are presented. The modeling studies described here allowed us to identify some differing structural features of the catalytic pockets that may be helpful in the development of active and more selective drugs to treat tumors found in different tissues while maintaining minimal side effects. © 2003 Wiley Periodicals, Inc. Int J Quantum Chem, 2004