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.

Design, Synthesis, and Molecular Docking Studies of a Conjugated Thiadiazole–Thiourea Scaffold as Antituberculosis Agents

“…[63][64][65][66][67][68][69] Antituberculosis activity were predicted for our compound set 5-20 within the range of 0.364<Pa<0.684. Although no direct correlation were observed between Pa values and MIC values, it was notable that most active three compounds had good Pa scores (Pa>0.5).…”

Computer-aided prediction of biological activity spectra for chemical compounds: opportunities and limitation

“…С целью поиска новых антигипертензивных веществ, обладающих дуальными механизмами действия, c использованием PASS было выполнено прогнозирование ассоциированных с этим эффектом 30 молекулярных механизмов действия для 183462 молекул из баз данных компаний AsInEx и ChemBridge [58]. Тестирование in vitro четырёх соединений, для которых было предсказано ингибирование ангиотензинконвертирующего фермента (ACE) и нейтральной эндопептидазы (NEP), подтвердило наличие у них прогнозируемых видов активности (для ACE значения IC 50 = 10 -7 -10 -9 M, для NEP значения IC 50 = 10 -5 M).…”

Gem-Diphosphonates: The Motif of Diverse Biological and Medicinal Importance

“…The CAMM (computer-assisted molecular modeling), PASS program [63,64], was adopted for designing in silico-the structures of potentially active molecules for synthesis. However, synthesis of bisphosphonate derivatives and the relevant bisphosphonic acid was recently discussed in detail in a recent review article [65].…”