title: Computer-aided selection of potential antihypertensive compounds with dual mechanism of action.
abstract: The prediction of biological activity spectra for substances as an approach for searching compounds with complex mechanisms of action was studied. New compounds with dual mechanisms of antihypertensive action were found by this approach. Biological activity spectra for substances were predicted on the basis of their structural formulas by the computer program PASS. Thirty molecular mechanisms of action of compounds from the MDDR 99.2 database, which cause the antihypertensive effect and can be predicted by PASS, have been identified. The analysis of predictions for compounds with 15 dual antihypertensive mechanisms of action from the MDDR 99.2 database has confirmed high accuracy of prediction. This approach was applied to databases of commercially available compounds (AsInEx and ChemBridge) and allowed us to select four substances that are potential inhibitors of angiotensin converting enzyme (ACE) and of neutral endopeptidase (NEP). At a later time, all these compounds were found to be the inhibitors of both ACE and NEP. The most potent compounds had IC(50) of 10(-7)-10(-9) M for ACE and 10(-5) M for NEP. New combinations of dual mechanisms of action never before found for antihypertensive compounds were predicted.
authors.affiliation: Institute of Biomedical Chemistry of Russian Academy of Medical Sciences, Pogodinskaya Street, 10, Moscow 119121, Russia. alex@ibmh.msk.su
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Lagunin
authors.forename: Oleg A
authors.initials: OA
authors.lastname: Gomazkov
authors.forename: Dmitrii A
authors.initials: DA
authors.lastname: Filimonov
authors.forename: Tatyana A
authors.initials: TA
authors.lastname: Gureeva
authors.forename: Elvira A
authors.initials: EA
authors.lastname: Dilakyan
authors.forename: Elena V
authors.initials: EV
authors.lastname: Kugaevskaya
authors.forename: Yulia E
authors.initials: YE
authors.lastname: Elisseeva
authors.forename: Nina I
authors.initials: NI
authors.lastname: Solovyeva
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Poroikov
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry*; D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry*; D001921:Brain / Q000201:enzymology; D002417:Cattle; D003201:Computers; D016208:Databases, Factual; D006801:Humans; D007672:Kidney Cortex / Q000201:enzymology; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry; D011336:Probability; D051381:Rats
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D007703:Peptidyl-Dipeptidase A; D015260:Neprilysin