Multiquery Similarity Searching Models: An Alternative Approach for Predicting Hemolytic Activity from Peptide Sequence.

The desirable pharmacological properties and a broad number of therapeutic activities have made peptides promising drugs over small organic molecules and antibody drugs. Nevertheless, toxic effects, such as hemolysis, have hampered the development of such promising drugs. Hence, a reliable computational tool to predict peptide hemolytic toxicity is enormously useful before synthesis and experimental evaluation. Currently, four web servers that predict hemolytic activity using machine learning (ML) algorithms are available; however, they exhibit some limitations, such as the need for a reliable negative set and limited application domain. Hence, we developed a robust model based on a novel theoretical approach that combines network science and a multiquery similarity searching (MQSS) method. A total of 1152 initial models were constructed from 144 scaffolds generated in a previous report. These were evaluated on external data sets, and the best models were fused and improved. Our best MQSS model I1 outperformed all state-of-the-art ML-based models and was used to characterize the prevalence of hemolytic toxicity on therapeutic peptides. Based on our model's estimation, the number of hemolytic peptides might be 3.9-fold higher than the reported.

Prediction of compound-target interaction using several artificial intelligence algorithms and comparison with a consensus-based strategy.

For understanding a chemical compound's mechanism of action and its side effects, as well as for drug discovery, it is crucial to predict its possible protein targets. This study examines 15 developed target-centric models (TCM) employing different molecular descriptions and machine learning algorithms. They were contrasted with 17 third-party models implemented as web tools (WTCM). In both sets of models, consensus strategies were implemented as potential improvement over individual predictions. The findings indicate that TCM reach f1-score values greater than 0.8. Comparing both approaches, the best TCM achieves values of 0.75, 0.61, 0.25 and 0.38 for true positive/negative rates (TPR, TNR) and false negative/positive rates (FNR, FPR); outperforming the best WTCM. Moreover, the consensus strategy proves to have the most relevant results in the top 20 % of target profiles. TCM consensus reach TPR and FNR values of 0.98 and 0; while on WTCM reach values of 0.75 and 0.24. The implemented computational tool with the TCM and their consensus strategy at: https://bioquimio.udla.edu.ec/tidentification01/ . Scientific Contribution: We compare and discuss the performances of 17 public compound-target interaction prediction models and 15 new constructions. We also explore a compound-target interaction prioritization strategy using a consensus approach, and we analyzed the challenging involved in interactions modeling.

Rethinking the applicability domain analysis in QSAR models.

Notwithstanding the wide adoption of the OECD principles (or best practices) for QSAR modeling, disparities between in silico predictions and experimental results are frequent, suggesting that model predictions are often too optimistic. Of these OECD principles, the applicability domain (AD) estimation has been recognized in several reports in the literature to be one of the most challenging, implying that the actual reliability measures of model predictions are often unreliable. Applying tree-based error analysis workflows on 5 QSAR models reported in the literature and available in the QsarDB repository, i.e., androgen receptor bioactivity (agonists, antagonists, and binders, respectively) and membrane permeability (highest membrane permeability and the intrinsic permeability), we demonstrate that predictions erroneously tagged as reliable (AD prediction errors) overwhelmingly correspond to instances in subspaces (cohorts) with the highest prediction error rates, highlighting the inhomogeneity of the AD space. In this sense, we call for more stringent AD analysis guidelines which require the incorporation of model error analysis schemes, to provide critical insight on the reliability of underlying AD algorithms. Additionally, any selected AD method should be rigorously validated to demonstrate its suitability for the model space over which it is applied. These steps will ultimately contribute to more accurate estimations of the reliability of model predictions. Finally, error analysis may also be useful in "rational" model refinement in that data expansion efforts and model retraining are focused on cohorts with the highest error rates.

Antifungal activity against Candida albicans of methyl 3,5-dinitrobenzoate loaded nanoemulsion.

The objective of this study was to evaluate the antifungal activity of free methyl 3,5 dinitrobenzoate (MDNB) and its nanoemulsion (MDNB-NE) against strains of Candida albicans. Additionally, a molecular modeling study was also carried out to propose the mechanism of action and toxicity of MDNB. These results demonstrated the MDNB-NE presented a droplet size of 181.16 ± 3.20 nm and polydispersity index of 0.30 ± 0.03. MDNB and MDNB-NE inhibited the growth of all strains with minimum inhibitory concentrations of 0.27-1.10 mM. The biological results corroborated the molecular model, which pointed to a multi-target antifungal mechanism of action for MDNB in C. albicans. The study could serve as a basis for further research involving compounds with nitro groups with antifungal.

Antileishmanial activity of 5-nitroindazole derivatives.

Background: Currently, there is no safe and effective vaccine against leishmaniasis and existing therapies are inadequate due to high toxicity, cost and decreased efficacy caused by the emergence of resistant parasite strains. Some indazole derivatives have shown in vitro and in vivo activity against Trichomonas vaginalis and Trypanosoma cruzi. On that basis, 20 indazole derivatives were tested in vitro against Leishmania amazonensis. Objective: To evaluate the in vitro activity of twenty 2-benzyl-5-nitroindazolin-3-one derivatives against L. amazonensis. Design: For the selection of promising compounds, it is necessary to evaluate the indicators for in vitro activity. For this aim, a battery of studies for antileishmanial activity and cytotoxicity were implemented. These results enabled the determination of the substituents in the indazole derivatives responsible for activity and selectivity, through the analysis of the structure-activity relationship (SAR). Methods: In vitro cytotoxicity against mouse peritoneal macrophages and growth inhibitory activity in promastigotes were evaluated for 20 compounds. Compounds that showed adequate selectivity were tested against intracellular amastigotes. The SAR from the results in promastigotes was represented using the SARANEA software. Results: Eight compounds showed selectivity index >10% and 50% inhibitory concentration <1 µM against the promastigote stage. Against intracellular amastigotes, four were as active as Amphotericin B. The best results were obtained for 2-(benzyl-2,3-dihydro-5-nitro-3-oxoindazol-1-yl) ethyl acetate, with 50% inhibitory concentration of 0.46 ± 0.01 µM against amastigotes and a selectivity index of 875. The SAR study showed the positive effect on the selectivity of the hydrophilic fragments substituted in position 1 of 2-benzyl-5- nitroindazolin-3-one, which played a key role in improving the selectivity profile of this series of compounds. Conclusion: 2-bencyl-5-nitroindazolin-3-one derivatives showed selective and potent in vitro activity, supporting further investigations on this family of compounds as potential antileishmanial hits.

Validation of venous thromboembolism predictive model in hematologic malignancies.

Although several scores stratify venous thromboembolism (VTE) risk in solid tumors, hematologic malignancies (HM) are underrepresented. To develop an internal and external validation of a logistic regression model to predict VTE risk in hospitalized HM patients. Validation of the existing VTE predictive model was performed through a prospective case-control study in 496 hospitalized HM patients between December 2010 and 2020 at the Arnaldo Milián University Hospital, Cuba. The predictive model designed with data from 285 patients includes 5 predictive factors: hypercholesterolemia, tumoral activity, use of thrombogenic drugs, diabetes mellitus, and immobilization. The model was internally validated using bootstrap analysis. External validation was realized in a prospective cohort of 211 HM patients. The predictive model had a 76.4% negative predictive value (NPV) and an 81.7% positive predictive value (PPV) in the bootstrapping validation. The area under curve (AUC) in the bootstrapping set was 0.838. Accuracy was 80.1% and 82.9% in the internal and external validation, respectively. In the external validation, the model produced 89.7% of NPV, 67.7% of PPV, 74.6% of sensitivity, and 86.2% of specificity. The AUC in the external validation was 0.900. VTE predictive model is a reproducible and simple tool with good accuracy and discrimination.

Elucidating the Racemization Mechanism of Aliphatic and Aromatic Amino Acids by In Silico Tools.

The racemization of biomolecules in the active site can reduce the biological activity of drugs, and the mechanism involved in this process is still not fully comprehended. The present study investigates the impact of aromaticity on racemization using advanced theoretical techniques based on density functional theory. Calculations were performed at the ωb97xd/6-311++g(d,p) level of theory. A compelling explanation for the observed aromatic stabilization via resonance is put forward, involving a carbanion intermediate. The analysis, employing Hammett's parameters, convincingly supports the presence of a negative charge within the transition state of aromatic compounds. Moreover, the combined utilization of natural bond orbital (NBO) analysis and intrinsic reaction coordinate (IRC) calculations confirms the pronounced stabilization of electron distribution within the carbanion intermediate. To enhance our understanding of the racemization process, a thorough examination of the evolution of NBO charges and Wiberg bond indices (WBIs) at all points along the IRC profile is performed. This approach offers valuable insights into the synchronicity parameters governing the racemization reactions.

Inducing Homochirality Through Intermediary Catalytic Species: A Stochastic Approach.

A new chiral amplification mechanism based on a stochastic approach is proposed. The mechanism includes five different chemical species, an achiral substrate (A), two chiral forms (L, D), and two intermediary species (LA, DA). The process occurs within a small, semipermeable compartment that can be diffusively coupled with the outside environment. The study considers two alternative primary sources for chiral species within the compartment, one chemical and the other diffusive. As a remarkable fact, the chiral amplification process occurs due to stochastic fluctuations of an intermediary catalytic species (LA, DA) produced in situ, given the interaction of the chiral species with the achiral substrate. The net process includes two different steps: the synthesis of the catalyst (LA and DA) and the catalytic production of new chiral species from the substrate. Stochastic simulations show that proper parameterization can induce a robust chiral state within the compartment regardless of whether the system is open or closed. We also show how an increase in the non-catalytic production of chiral species tends to negatively impact the homochirality degree of the system. By its conception, the proposed mechanism suggests a deeper connection with how most biochemical processes occur in living beings, a fact that could open new avenues for studying this fascinating phenomenon.

Degradation of PET Bottles by an Engineered Ideonella sakaiensis PETase.

Extensive plastic production has become a serious environmental and health problem due to the lack of efficient treatment of plastic waste. Polyethylene terephthalate (PET) is one of the most used polymers and is accumulating in landfills or elsewhere in nature at alarming rates. In recent years, enzymatic degradation of PET by Ideonella sakaiensis PETase (IsPETase), a cutinase-like enzyme, has emerged as a promising strategy to completely depolymerize this polymer into its building blocks. Here, inspired by the architecture of cutinases and lipases homologous to IsPETase and using 3D structure information of the enzyme, we rationally designed three mutations in IsPETase active site for enhancing its PET-degrading activity. In particular, the S238Y mutant, located nearby the catalytic triad, showed a degradation activity increased by 3.3-fold in comparison to the wild-type enzyme. Importantly, this structural modification favoured the function of the enzyme in breaking down highly crystallized (~31%) PET, which is found in commercial soft drink bottles. In addition, microscopical analysis of enzyme-treated PET samples showed that IsPETase acts better when the smooth surface of highly crystalline PET is altered by mechanical stress. These results represent important progress in the accomplishment of a sustainable and complete degradation of PET pollution.

Antileishmanial Activity of Cinnamic Acid Derivatives against Leishmania infantum.

Leishmania infantum is the etiological agent of visceral leishmaniasis (VL) in South America, the Mediterranean basin, and West and Central Asia. The most affected country, Brazil, reported 4297 VL cases in 2017. L. infantum is transmitted by female phlebotomine sand flies during successive blood meals. There are no validated vaccines to prevent the infection and the treatment relies on drugs that often present severe side effects, which justify the efforts to find new antileishmanial drugs. Cinnamic acid derivatives have shown several pharmacological activities, including antiparasitic action. Therefore, in the present study, the biological evaluation of cinnamic acid and thirty-four derivatives against L. infantum is reported. The compounds were prepared by several synthesis methods and characterized by spectroscopic techniques and high-resolution mass spectrometry. The results revealed that compound 32 (N-(4-isopropylbenzyl)cinnamamide) was the most potent antileishmanial agent (IC50 = 33.71 µM) with the highest selectivity index (SI > 42.46), followed by compound 15 (piperonyl cinnamate) with an IC50 = 42.80 µM and SI > 32.86. Compound 32 was slightly less potent and nineteen times more selective for the parasite than amphotericin B (MIC = 3.14 uM; SI = 2.24). In the molecular docking study, the most likely target for the compound in L. infantum was aspartyl aminopeptidase, followed by aldehyde dehydrogenase, mitochondrial. The data obtained show the antileishmanial potential of this class of compounds and may be used in the search for new drug candidates against Leishmania species.

Molecular Modeling and In Vitro Evaluation of Piplartine Analogs against Oral Squamous Cell Carcinoma.

Cancer is a principal cause of death in the world, and providing a better quality of life and reducing mortality through effective pharmacological treatment remains a challenge. Among malignant tumor types, squamous cell carcinoma-esophageal cancer (EC) is usually located in the mouth, with approximately 90% located mainly on the tongue and floor of the mouth. Piplartine is an alkamide found in certain species of the genus Piper and presents many pharmacological properties including antitumor activity. In the present study, the cytotoxic potential of a collection of piplartine analogs against human oral SCC9 carcinoma cells was evaluated. The analogs were prepared via Fischer esterification reactions, alkyl and aryl halide esterification, and a coupling reaction with PyBOP using the natural compound 3,4,5-trimethoxybenzoic acid as a starting material. The products were structurally characterized using 1H and 13C nuclear magnetic resonance, infrared spectroscopy, and high-resolution mass spectrometry for the unpublished compounds. The compound 4-methoxy-benzyl 3,4,5-trimethoxybenzoate (9) presented an IC50 of 46.21 µM, high selectively (SI > 16), and caused apoptosis in SCC9 cancer cells. The molecular modeling study suggested a multi-target mechanism of action for the antitumor activity of compound 9 with CRM1 as the main target receptor.

Synthetic Cinnamides and Cinnamates: Antimicrobial Activity, Mechanism of Action, and In Silico Study.

The severity of infectious diseases associated with the resistance of microorganisms to drugs highlights the importance of investigating bioactive compounds with antimicrobial potential. Therefore, nineteen synthetic cinnamides and cinnamates having a cinnamoyl nucleus were prepared and submitted for the evaluation of antimicrobial activity against pathogenic fungi and bacteria in this study. To determine the minimum inhibitory concentration (MIC) of the compounds, possible mechanisms of antifungal action, and synergistic effects, microdilution testing in broth was used. The structures of the synthesized products were characterized with FTIR spectroscopy, 1 H-NMR, 13 C-NMR, and HRMS. Derivative 6 presented the best antifungal profile, suggesting that the presence of the butyl substituent potentiates its biological response (MIC = 626.62 µM), followed by compound 4 (672.83 µM) and compound 3 (726.36 µM). All three compounds were fungicidal, with MFC/MIC ≤ 4. For mechanism of action, compounds 4 and 6 directly interacted with the ergosterol present in the fungal plasmatic membrane and with the cell wall. Compound 18 presented the best antibacterial profile (MIC = 458.15 µM), followed by compound 9 (550.96 µM) and compound 6 (626.62 µM), which suggested that the presence of an isopropyl group is important for antibacterial activity. The compounds were bactericidal, with MBC/MIC ≤ 4. Association tests were performed using the Checkerboard method to evaluate potential synergistic effects with nystatin (fungi) and amoxicillin (bacteria). Derivatives 6 and 18 presented additive effects. Molecular docking simulations suggested that the most likely targets of compound 6 in C. albicans were caHOS2 and caRPD3, while the most likely target of compound 18 in S. aureus was saFABH. Our results suggest that these compounds could be used as prototypes to obtain new antimicrobial drugs.

Critical Review of Plant-Derived Compounds as Possible Inhibitors of SARS-CoV-2 Proteases: A Comparison with Experimentally Validated Molecules.

Ever since coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, was declared a pandemic on March 11, 2020, by the WHO, a concerted effort has been made to find compounds capable of acting on the virus and preventing its replication. In this context, researchers have refocused part of their attention on certain natural compounds that have shown promising effects on the virus. Considering the importance of this topic in the current context, this study aimed to present a critical review and analysis of the main reports of plant-derived compounds as possible inhibitors of the two SARS-CoV-2 proteases: main protease (Mpro) and Papain-like protease (PLpro). From the search in the PubMed database, a total of 165 published articles were found that met the search patterns. A total of 590 unique molecules were identified from a total of 122 articles as potential protease inhibitors. At the same time, 114 molecules reported as natural products and with annotation of theoretical support and antiviral effects were extracted from the COVID-19 Help database. After combining the molecules extracted from articles and those obtained from the database, we identified 648 unique molecules predicted as potential inhibitors of Mpro and/or PLpro. According to our results, several of the predicted compounds with higher theoretical confidence are present in many plants used in traditional medicine and even food, such as flavonoids, carboxylic acids, phenolic acids, triterpenes, terpenes phytosterols, and triterpenoids. These are potential inhibitors of Mpro and PLpro. Although the predictions of several molecules against SARS-CoV-2 are promising, little experimental information was found regarding certain families of compounds. Only 45 out of the 648 unique molecules have experimental data validating them as inhibitors of Mpro or PLpro, with the most frequent scaffold present in these 45 compounds being the flavone. The novelty of this work lies in the analysis of the structural diversity of the chemical space among the molecules predicted as inhibitors of SARS-CoV-2 Mpro and PLpro proteases and the comparison to those molecules experimentally validated. This work emphasizes the need for experimental validation of certain families of compounds, preferentially combining classical enzymatic assays with interaction-based methods. Furthermore, we recommend checking the presence of Pan-Assay Interference Compounds (PAINS) and the presence of molecules previously reported as inhibitors of Mpro or PLpro to optimize resources and time in the discovery of new SARS-CoV-2 antivirals from plant-derived molecules.

Synthesis of Coumarin and Homoisoflavonoid Derivatives and Analogs: The Search for New Antifungal Agents.

A set of twenty-four synthetic derivatives, with coumarin and homoisoflavonoid cores and structural analogs, were submitted for evaluation of antifungal activity against various species of Candida. The broth microdilution test was used to determine the Minimum Inhibitory Concentration (MIC) of the compounds and to verify the possible antifungal action mechanisms. The synthetic derivatives were obtained using various reaction methods, and six new compounds were obtained. The structures of the synthesized products were characterized by FTIR spectroscopy: 1H-NMR, 13C-NMR, and HRMS. The coumarin derivative 8 presented the best antifungal profile, suggesting that the pentyloxy substituent at the C-7 position of coumarin ring could potentiate the bioactivity. Compound 8 was then evaluated against the biofilm of C. tropicalis ATCC 13803, which showed a statistically significant reduction in biofilm at concentrations of 0.268 µmol/mL and 0.067 µmol/mL, when compared to the growth control group. For a better understanding of their antifungal activity, compounds 8 and 21 were submitted to a study of the mode of action on the fungal cell wall and plasma membrane. It was observed that neither compound interacted directly with ergosterol present in the fungal plasma membrane or with the fungal cell wall. This suggests that their bioactivity was due to interaction involving other pharmacological targets. Compound 8 was also subjected to a molecular modeling study, which showed that its antifungal action mechanism occurred mainly through interference in the redox balance of the fungal cell, and by compromising the plasma membrane; not by direct interaction, but by interference in ergosterol synthesis. Another important finding was the antifungal capacity of homoisoflavonoids 23 and 24. Derivative 23 presented slightly higher antifungal activity, possibly due to the presence of the methoxyl substituent in the meta position in ring B.

Cytotoxic and Antifungal Amides Derived from Ferulic Acid: Molecular Docking and Mechanism of Action.

Amides derived from ferulic acid have a wide spectrum of pharmacological activities, including antitumor and antifungal activity. In the present study, a series of ten amides were obtained by coupling reactions using the reagents (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyBOP) and N,N'-dicyclohexylcarbodiimide (DCC). All the compounds were identified on the basis of their IR, 1H- and 13C-NMR, HRMS data, and with yields ranging from 43.17% to 91.37%. The compounds were subjected to cytotoxic tests by the alamar blue technique and antifungal screening by the broth microdilution method to determine the minimum inhibitory concentration (MIC). The amides 10 and 11 displayed the best result in both biological evaluations, and compound 10 was the most potent and selective in HL-60 cancer cells, with no cytotoxicity on healthy cells. This amide had antifungal activity in all strains and had the lowest MIC against Candida albicans and Candida tropicalis. The possible mechanism of antifungal action occurs via the fungal cell wall. Molecular modeling suggested that compounds 10 and 11 interact with the enzymes GWT1 and GSC1, which are essential for the development of C. albicans. The findings of the present study demonstrated that compounds 10 and 11 may be used as a platform in drug development in the future.

In silico Analyses of Immune System Protein Interactome Network, Single-Cell RNA Sequencing of Human Tissues, and Artificial Neural Networks Reveal Potential Therapeutic Targets for Drug Repurposing Against COVID-19.

Background: There is pressing urgency to identify therapeutic targets and drugs that allow treating COVID-19 patients effectively. Methods: We performed in silico analyses of immune system protein interactome network, single-cell RNA sequencing of human tissues, and artificial neural networks to reveal potential therapeutic targets for drug repurposing against COVID-19. Results: We screened 1,584 high-confidence immune system proteins in ACE2 and TMPRSS2 co-expressing cells, finding 25 potential therapeutic targets significantly overexpressed in nasal goblet secretory cells, lung type II pneumocytes, and ileal absorptive enterocytes of patients with several immunopathologies. Then, we performed fully connected deep neural networks to find the best multitask classification model to predict the activity of 10,672 drugs, obtaining several approved drugs, compounds under investigation, and experimental compounds with the highest area under the receiver operating characteristics. Conclusion: After being effectively analyzed in clinical trials, these drugs can be considered for treatment of severe COVID-19 patients. Scripts can be downloaded at https://github.com/muntisa/immuno-drug-repurposing-COVID-19.

A population-based study of preeclampsia and eclampsia in Ecuador: ethnic, geographical and altitudes differences.

BACKGROUND: In Ecuador eclampsia and preeclampsia were identified as the third cause of maternal death. Like other Latin-American countries, Ecuador has human settlements living from 0 to more than 4000 m of altitude and comprising a wide ethnic-diversity across all these altitude changes. These characteristics offer the possibility to study a wide variety of possible risk factors for preeclampsia and eclampsia. METHODS: We conducted a population-based retrospective study of all deliveries in Ecuador from 2015 through 2017. The main variables analyzed were: altitude, ethnic self-identification, geographic location, and maternal age. The data comes from the Ecuadorian National Institute of Statistics and Census (INEC) and the Ecuadorian Ministry of Health. Data information regarding maternal parity and socioeconomic status was not available from official records. Logistic regression analysis was used to study the relationship between preeclampsia and eclampsia with the variable of interest. Geospatial statistical analysis was done to identify statistically significant spatial clusters of preeclampsia and eclampsia cases. RESULTS: The incidence of preeclampsia was estimated between 5.11 (5.05-5.18) and 6.23 (6.16-6.30), and 0.25 (0.23-0.26) for eclampsia. Native American have a lower incidence regarding preeclampsia compared to other ethnic groups. High altitude has a significant odds ratio (OR = 2.31, 1.93-2.78) of preeclampsia. Montubio residing in middle altitude (1500-3500 m) have the highest risk of preeclampsia (OR = 18.13, 9.53-34.50). Afro-Ecuadorians also have an increased risk of preeclampsia associated with altitude (OR = 2.36, 1.78-3.14). Ethnicity was not identified as a risk factor for eclampsia. Early and older maternal age was associated with an increased risk of preeclampsia and eclampsia. Women living more than 20 km from the obstetric unit have an OR = 2.61 (2.32-2.95, p-value< 0.01) and OR = 1.87 (1.82-1.92, p-value< 0.01) of developing eclampsia and preeclampsia respectively. CONCLUSIONS: Preeclampsia is widespread across low and high-altitude areas, while eclampsia is mostly located at lower altitudes. Montubios living at middle or high altitudes represents the ethnic group with a higher risk of preeclampsia. No ethnic effect was identified as a potential risk factor for eclampsia. Moreover, in eclampsia the associated risk of young women seems to be higher than in preeclampsia.

A Multi-Objective Approach for Drug Repurposing in Preeclampsia.

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.

Bioactive Terpenes and Their Derivatives as Potential SARS-CoV-2 Proteases Inhibitors from Molecular Modeling Studies.

The coronavirus disease 2019 (COVID-19) pandemic is caused by a novel coronavirus; the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Millions of cases and deaths to date have resulted in a global challenge for healthcare systems. COVID-19 has a high mortality rate, especially in elderly individuals with pre-existing chronic comorbidities. There are currently no effective therapeutic approaches for the prevention and treatment of COVID-19. Therefore, the identification of effective therapeutics is a necessity. Terpenes are the largest class of natural products that could serve as a source of new drugs or as prototypes for the development of effective pharmacotherapeutic agents. In the present study, we discuss the antiviral activity of these natural products and we perform simulations against the Mpro and PLpro enzymes of SARS-CoV-2. Our results strongly suggest the potential of these compounds against human coronaviruses, including SARS-CoV-2.

Antifungal Activity of N-(4-Halobenzyl)amides against Candida spp. and Molecular Modeling Studies.

Fungal infections remain a high-incidence worldwide health problem that is aggravated by limited therapeutic options and the emergence of drug-resistant strains. Cinnamic and benzoic acid amides have previously shown bioactivity against different species belonging to the Candida genus. Here, 20 cinnamic and benzoic acid amides were synthesized and tested for inhibition of C. krusei ATCC 14243 and C. parapsilosis ATCC 22019. Five compounds inhibited the Candida strains tested, with compound 16 (MIC = 7.8 µg/mL) producing stronger antifungal activity than fluconazole (MIC = 16 µg/mL) against C. krusei ATCC 14243. It was also tested against eight Candida strains, including five clinical strains resistant to fluconazole, and showed an inhibitory effect against all strains tested (MIC = 85.3-341.3 µg/mL). The MIC value against C. krusei ATCC 6258 was 85.3 mcg/mL, while against C. krusei ATCC 14243, it was 10.9 times smaller. This strain had greater sensitivity to the antifungal action of compound 16. The inhibition of C. krusei ATCC 14243 and C. parapsilosis ATCC 22019 was also achieved by compounds 2, 9, 12, 14 and 15. Computational experiments combining target fishing, molecular docking and molecular dynamics simulations were performed to study the potential mechanism of action of compound 16 against C. krusei. From these, a multi-target mechanism of action is proposed for this compound that involves proteins related to critical cellular processes such as the redox balance, kinases-mediated signaling, protein folding and cell wall synthesis. The modeling results might guide future experiments focusing on the wet-lab investigation of the mechanism of action of this series of compounds, as well as on the optimization of their inhibitory potency.