RESUMO

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.

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RESUMO

Resumen La pandemia por SARS-CoV-2 evidencia la importancia del trabajo conjunto para el desarrollo de vacunas contra el virus, estas incluyen virus completos, subunidades, vacunas atenuadas, vectores virales y ácidos nucleicos, la mayoría de propuestas están basadas en subunidades proteicas. De los más de 115 candidatos reportados hasta abril, 73 se encuentran en estudios preclínicos, a junio la opción más avanzada se ubica en fase II/II, una en fase II, dos en fase I/II y cuatro en fase I. Los candidatos más avanzados son AZD1222 (AstraZeneca) basada en adenovirus recombinante para la proteína S (fase II/III); PiCoVacc (Sinovac Biotech) basada en virus inactivado (fase I/II); mientras que mRNA-1273 (Moderna) basada en ARNm para la proteína S, INO-4800 (Inovio Pharmaceticals) basada en DNA plasmídico para proteína S, Ad5-nCoV (Cansino Biologicals) basada en adenovirus tipo 5 expresando la proteína S, LV-SMENP-DC basada en células dendríticas con lentivirus para dominios de proteínas virales y aAPC patógeno-específica, basada en células presentadoras de antígenos con lentivirus para dominios de proteínas virales (ambas de Shenzhen Geno-Immune Medical Institute, se encuentran en fase I). La finalidad de este trabajo contrarreloj se dirige hacia el único objetivo de lograr un candidato a vacuna que demuestre seguridad y efectividad en el control y prevención del virus sorpresivo que dejó al descubierto que no hay enemigo pequeño o que mientras más pequeño más peligroso, pues el causante de COVID-19 no solo atacó la salud humana sino la economía del planeta y las costumbres y actividades rutinarias que desarrollaba la humanidad.

ABSTRACT The SARS-CoV-2 pandemic shows the importance of joint work for the development of vaccines against the virus, these include complete viruses, subunits, attenuated vaccines, viral vectors and nucleic acids, most of the proposals are based on protein subunits. Of the more than 115 candidates reported until April, 73 are in preclinical studies, as of June the most advanced option is in phase II / II, one in phase II, two in phase I / II and four in phase I. The candidates more advanced are AZD1222 (AstraZeneca) based on recombinant adenovirus for protein S (phase II / III); PiCoVacc (Sinovac Biotech) based on inactivated virus (Phase I / II); while mRNA-1273 (Modern) based on mRNA for protein S, INO-4800 (Inovio Pharmaceticals) based on plasmid DNA for protein S, Ad5-nCoV (Cansino Biologicals) based on adenovirus type 5 expressing protein S, LV- SMENP-DC is based on dendritic cells with lentiviruses for viral protein domains and pathogen-specified aAPC, based on antigen-presenting cells with lentiviruses for viral protein domains (Shenzhen Institute of Genoimmune Medicine, are in phase I). The purpose of this work against the clock is directed towards the sole objective of achieving a vaccine candidate who demonstrates safety and determination in the control and prevention of the surprising virus that revealed that there is no small enemy or that the smaller the more dangerous, because the cause of COVID-19 not only attacked human health but the economy of the planet and the customs and routine activities that humanity develops.

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