i. Patents

DDT 2002: Drug Discovery Using Search Engines Derived From Gene Structure And Stereochemically Accurate Databases.

Lawrence B. Hendry, Douglas E. Ewing, Tim Scott, Edwin D. Bransome, Jr., E. Howard Merry and Virendra B. Mahesh. Accelerated Pharmaceuticals Inc., P.O. Box 1667, 1025 Broad Street, Augusta, GA 30903 Web Site: www.accpharm.net; E-Mail: lbh@mail.accpharm.com; ehm@mail.accpharm.com; Phone: 706-821-3615

Identifying successful drug candidates is critical to the ultimate success of the pharmaceutical industry. Given that patent protection for many widely prescribed drugs has lapsed or will expire shortly coupled with unanticipated side effects of certain existing drugs and drug candidates, there is intense pressure to get more new chemical entities into the pipeline. This situation exists despite the relatively recent development of widely recognized drug discovery tools such as high throughput screening, combinatorial chemistry and in silico screening. With regard to the latter, a rational screening method coupled with databases containing accurate structures is essential to the successful identification of safe and effective drug candidates.

Accelerated Pharmaceuticals Inc. (API) has developed proprietary in silico drug discovery technology that employs information derived from interactions of small molecule ligands with macromolecules notably nucleic acids and/or nucleic acid-receptor protein complexes. The complexes were used to construct three dimensional search engines derived from the composite structure of known active ligands and features of the macromolecules. In some cases, x-ray crystallographic data have been employed e.g. certain antibiotics and antineoplastic drugs which have been shown to intercalate into DNA. Search engines have also been created for compounds shown by modeling to fit particularly well into DNA e.g. estrogens, androgens, thyroid hormone, glucocorticoids, oral thiazolidinediones antidiabetic drugs. Databases containing stereochemically accurate molecules have been constructed. Such databases include those in which all molecules have been tested for a given biological activity thereby enabling an accurate determination of enrichment rates (hits of active compounds/number of compounds searched).

Here, we demonstrate the application of the estrogen, androgen, antidepressant, sedative and antibiotic (Anthrax) search engines to drug discovery. The search engines were derived from the fit of active ligands into a scaffold derived from partially unwound gene sequences in double stranded DNA and/or gene/nuclear protein interfaces. Sybyl/Unity molecular modeling software (Tripos Associates, Inc, St. Louis, MO) was employed. Each search engine is composed of: 1) electrostatic spatials which reflect positions in space of hydrogen bonds between the ligands and macromolecules; 2) an excluded volume which represents the macromolecule surface; and 3) an included volume that is the composite surface of active ligands aligned by fit into the site. In order to be considered a hit, a candidate molecule must contain hydrogen bonding functional groups that fit within the electrostatic spatials and fit within the included volume without violating the excluded volume. The estrogen search engine was employed to benchmark the reproducibility and accuracy of the methodology. A stereochemically accurate database of approximately 1500 compounds previously tested in vivo by NIH for estrogenic (uterotropic) activity was constructed. Using the estrogen search engine, all active compounds were found to be hits with the exceptions being prodrugs known or thought to be metabolized to active compounds (e.g. esters); in such cases, the metabolite was a hit. The overall enrichment rate was approximately 30 fold. Hits generated by searching other databases included a wide diversity of structures unlike those used to create the search engine e.g. non steroidal compounds including phytoestrogens. A novel estrogenic compound designed at API (PDC-7) which is 2-3 times more active that the natural estrogen estradiol in vivo also hit the search engine (Medicinal Chemistry Research 10:440-455, 2001). Searches of generic databases with the estrogen, androgen, antidepressant, sedative and Anthrax search engines revealed a high percentage of hits with known activity as well as a high degree of selectivity. To our knowledge, no other drug discovery technology has demonstrated such levels of precision, accuracy, specificity or enrichment rates.