Abstract
Preeclampsia is a hypertensive disorder that occurs during pregnancy. It is a complex disease with unknown pathogenesis and the leading cause of fetal and maternal mortality during pregnancy. Using all drugs currently under clinical trial for preeclampsia, we extracted all their possible targets from the DrugBank and ChEMBL databases and labeled them as “targets”. The proteins labeled as “off-targets” were extracted in the same way but while taking all antihypertensive drugs which are inhibitors of ACE and/or angiotensin receptor antagonist as query molecules. Classification models were obtained for each of the 55 total proteins (45 targets and 10 off-targets) using the TPOT pipeline optimization tool. The average accuracy of the models in predicting the external dataset for targets and off-targets was 0.830 and 0.850, respectively. The combinations of models maximizing their virtual screening performance were explored by combining the desirability function and genetic algorithms. The virtual screening performance metrics for the best model were: the Boltzmann-Enhanced Discrimination of ROC (BEDROC)α=160.9 = 0.258, the Enrichment Factor (EF)1% = 31.55 and the Area Under the Accumulation Curve (AUAC) = 0.831. The most relevant targets for preeclampsia were: AR, VDR, SLC6A2, NOS3 and CHRM4, while ABCG2, ERBB2, CES1 and REN led to the most relevant off-targets. A virtual screening of the DrugBank database identified estradiol, estriol, vitamins E and D, lynestrenol, mifrepristone, simvastatin, ambroxol, and some antibiotics and antiparasitics as drugs with potential application in the treatment of preeclampsia.
Highlights
Preeclampsia is a complex pregnancy related disease with unknown pathogenesis
From the 19 drugs obtained from the ClinicalTrials for preeclampsia treatment or management and from the 41 antihypertensive drugs following the ACE inhibition and angiotensin receptor antagonist mechanisms, we obtained 155 unique proteins combining DrugBank and ChEMBL information
From these 45 targets, 10 are common to both groups. These common proteins are: EGFR, PHG1, SLC6A2, PPARG, ADORA3, CYP2C9, CYP3A4, CYP2C19, ABCB1 and CYP2C8. This means that some drugs used in preeclampsia share targets with those used for hypertension treatment
Summary
Preeclampsia is a complex pregnancy related disease with unknown pathogenesis. During pregnancy, preeclampsia appears after 20 weeks of gestation in two possible scenarios: early or late preeclampsia onset [1]. Preeclampsia is the leading cause of fetal and maternal mortality during pregnancy This is why better diagnosis strategies (early diagnosis) and exploration of new drugs for preeclampsia management are needed. The first option includes the use of low-dose aspirin in women with high risk of preeclampsia [2], the use of magnesium sulfate [3] and the administration of vitamin D [4,5]. Drugs in the latter group could extend the gestational age, increasing the chances of fetal growth and maturity to facilitate a safer delivery. The effectiveness of the treatment depends on the disease progression, but eventually delivery is the only definitive treatment for preeclampsia [1,6,7]
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