TATA-Binding Protein-Based Virtual Screening of FDA Drugs Identified New Anti-Giardiasis Agents.

Parasitic diseases, predominantly prevalent in developing countries, are increasingly spreading to high-income nations due to shifting migration patterns. The World Health Organization (WHO) estimates approximately 300 million annual cases of giardiasis. The emergence of drug resistance and associated side effects necessitates urgent research to address this growing health concern. In this study, we evaluated over eleven thousand pharmacological compounds sourced from the FDA database to assess their impact on the TATA-binding protein (TBP) of the early diverging protist Giardia lamblia, which holds medical significance. We identified a selection of potential pharmacological compounds for combating this parasitic disease through in silico analysis, employing molecular modeling techniques such as homology modeling, molecular docking, and molecular dynamics simulations. Notably, our findings highlight compounds DB07352 and DB08399 as promising candidates for inhibiting the TBP of Giardia lamblia. Also, these compounds and DB15584 demonstrated high efficacy against trophozoites in vitro. In summary, this study identifies compounds with the potential to combat giardiasis, offering the prospect of specific therapies and providing a robust foundation for future research.

Molecular Docking-Based Virtual Screening of FDA-Approved Drugs Using Trypanothione Reductase Identified New Trypanocidal Agents.

American trypanosomiasis or Chagas disease, caused by Trypanosoma cruzi (T. cruzi), affects approximately 6-7 million people worldwide. However, its pharmacological treatment causes several uncomfortable side effects, causing patients' treatment abandonment. Therefore, there is a need for new and better treatments. In this work, the molecular docking of nine hundred twenty-four FDA-approved drugs on three different sites of trypanothione reductase of T. cruzi (TcTR) was carried out to find potential trypanocidal agents. Finally, biological evaluations in vitro and in vivo were conducted with the selected FDA-approved drugs. Digoxin, alendronate, flucytosine, and dihydroergotamine showed better trypanocidal activity than the reference drugs benznidazole and nifurtimox in the in vitro evaluation against the trypomastigotes form. Further, these FDA-approved drugs were able to reduce 20-50% parasitemia in a short time in an in vivo model, although with less efficiency than benznidazole. Therefore, the results suggest a combined therapy of repurposed and canonical drugs against T. cruzi infection.

Ligand-Based Virtual Screening, Molecular Docking, and Molecular Dynamic Simulations of New ß-Estrogen Receptor Activators with Potential for Pharmacological Obesity Treatment.

Obesity is a pandemic and a serious health problem in developed and undeveloped countries. Activation of estrogen receptor beta (ERß) has been shown to promote weight loss without modifying caloric intake, making it an attractive target for developing new drugs against obesity. This work aimed to predict new small molecules as potential ERß activators. A ligand-based virtual screening of the ZINC15, PubChem, and Molport databases by substructure and similarity was carried out using the three-dimensional organization of known ligands as a reference. A molecular docking screening of FDA-approved drugs was also conducted as a repositioning strategy. Finally, selected compounds were evaluated by molecular dynamic simulations. Compounds 1 (-24.27 ± 0.34 kcal/mol), 2 (-23.33 ± 0.3 kcal/mol), and 6 (-29.55 ± 0.51 kcal/mol) showed the best stability on the active site in complex with ERß with an RMSD < 3.3 Å. RMSF analysis showed that these compounds do not affect the fluctuation of the Cα of ERß nor the compactness according to the radius of gyration. Finally, an in silico evaluation of ADMET showed they are safe molecules. These results suggest that new ERß ligands could be promising molecules for obesity control.

Ligand-based virtual screening, molecular docking, and molecular dynamics of eugenol analogs as potential acetylcholinesterase inhibitors with biological activity against Spodoptera frugiperda.

The development of new, more selective, environmental-friendly insecticide alternatives is in high demand for the control of Spodoptera frugiperda (S. frugiperda). The major objective of this work was to search for new potential S. frugiperda acetylcholinesterase (AChE) inhibitors. A ligand-based virtual screening was initially carried out considering six scaffolds derived from eugenol and the ZINC15, PubChem, and MolPort databases. Subsequently, molecular docking analysis of the selected compounds on the active site and a second region (determined by blind molecular docking) of the AChE of S. frugiperda was performed. Molecular dynamics and Molecular Mechanics Poisson-Boltzmann Surface Area analyses were also applied to improve the docking results. Finally, three new eugenol analogs were evaluated in vitro against S. frugiperda larvae. The virtual screening identified 1609 compounds from the chemical libraries. Control compounds were selected from the interaction fingerprint by molecular docking. Only three new eugenol analogs (1, 3, and 4) were stable at 50 ns by molecular dynamics. Compounds 1 and 4 had the best biological activity by diet (LC50 = 0.042 mg/mL) and by topical route (LC50 = 0.027 mg/mL), respectively. At least three new eugenol derivatives possessed good-to-excellent insecticidal activity against S. frugiperda.

Ligand-Based Virtual Screening and Molecular Docking of Benzimidazoles as Potential Inhibitors of Triosephosphate Isomerase Identified New Trypanocidal Agents.

Trypanosoma cruzi (T. cruzi) is a parasite that affects humans and other mammals. T. cruzi depends on glycolysis as a source of adenosine triphosphate (ATP) supply, and triosephosphate isomerase (TIM) plays a key role in this metabolic pathway. This enzyme is an attractive target for the design of new trypanocidal drugs. In this study, a ligand-based virtual screening (LBVS) from the ZINC15 database using benzimidazole as a scaffold was accomplished. Later, a molecular docking on the interface of T. cruzi TIM (TcTIM) was performed and the compounds were grouped by interaction profiles. Subsequently, a selection of compounds was made based on cost and availability for in vitro evaluation against blood trypomastigotes. Finally, the compounds were analyzed by molecular dynamics simulation, and physicochemical and pharmacokinetic properties were determined using SwissADME software. A total of 1604 molecules were obtained as potential TcTIM inhibitors. BP2 and BP5 showed trypanocidal activity with half-maximal lytic concentration (LC50) values of 155.86 and 226.30 µM, respectively. Molecular docking and molecular dynamics simulation analyzes showed a favorable docking score of BP5 compound on TcTIM. Additionally, BP5 showed a low docking score (-5.9 Kcal/mol) on human TIM compared to the control ligand (-7.2 Kcal/mol). Both compounds BP2 and BP5 showed good physicochemical and pharmacokinetic properties as new anti-T. cruzi agents.

Insecticidal Activity of Organic Extracts of Solidago graminifolia and Its Main Metabolites (Quercetin and Chlorogenic Acid) against Spodoptera frugiperda: An In Vitro and In Silico Approach.

Spodoptera frugiperda (S. frugiperda) remains a global primary pest of maize. Therefore, new options to combat this pest are necessary. In this study, the insecticidal activity of three crude foliar extracts (ethanol, dichloromethane, and hexane) and their main secondary metabolites (quercetin and chlorogenic acid) of the species Solidago graminifolia (S. graminifolia) by ingestion bioassays against S. frugiperda larvae was analyzed. Additionally, the extracts were phytochemically elucidated by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) analysis. Finally, an in silico study of the potential interaction of quercetin on S. frugiperda acetylcholinesterase was performed. Organic extracts were obtained in the range from 5 to 33%. The ethanolic extract caused higher mortality (81%) with a half-maximal lethal concentration (LC50) of 0.496 mg/mL. Flavonoid secondary metabolites such as hyperoside, quercetin, isoquercetin, kaempferol, and avicularin and some phenolic acids such as chlorogenic acid, solidagoic acid, gallic acid, hexoside, and rosmarinic acid were identified. In particular, quercetin had an LC50 of 0.157 mg/mL, and chlorogenic acid did not have insecticidal activity but showed an antagonistic effect on quercetin. The molecular docking analysis of quercetin on the active site of S. frugiperda acetylcholinesterase showed a -5.4 kcal/mol binding energy value, lower than acetylcholine and chlorpyrifos (-4.45 and -4.46 kcal/mol, respectively). Additionally, the interactions profile showed that quercetin had π-π interactions with amino acids W198, Y235, and H553 on the active site.

Weather influences on zoo visitation (Cabárceno, Northern Spain).

The general relationship between weather and climate with recreation and tourism has been widely acknowledged, but research on more activity-specific assessments is still required. The links between atmospheric conditions and visitation to the Nature Park of Cabárceno, an outdoor zoo located in Cantabria (Northern Spain), have been analyzed by conducting in situ surveys and comparing the daily number of attendants and meteorological parameters from a nearby weather station. The sensitivity of zoo visitation to weather variability was seasonally dependent, so winter attendance is directly related to the frequency of dry, warm, calm, and cloudless days; in summer, attendance was less sensitive to weather, with visitors attending in largest numbers during mild, cloudy, and breezy days. Moreover, a dissociation exists between perception and behavior during the period of the largest influx of visitors: visitors remark the importance of weather when planning the activity, but they show little flexibility when visiting. Socio-economic factors (origin of visitors, family structure) fade the weather influence.

In Silico Study of the Resistance to Organophosphorus Pesticides Associated with Point Mutations in Acetylcholinesterase of Lepidoptera: B. mandarina, B. mori, C. auricilius, C. suppressalis, C. pomonella, H. armígera, P. xylostella, S. frugiperda, and S. litura.

An in silico analysis of the interaction between the complex-ligands of nine acetylcholinesterase (AChE) structures of Lepidopteran organisms and 43 organophosphorus (OPs) pesticides with previous resistance reports was carried out. To predict the potential resistance by structural modifications in Lepidoptera insects, due to proposed point mutations in AChE, a broad analysis was performed using computational tools, such as homology modeling and molecular docking. Two relevant findings were revealed: (1) Docking results give a configuration of the most probable spatial orientation of two interacting molecules (AChE enzyme and OP pesticide) and (2) a predicted ΔGb. The mutations evaluated in the form 1 acetylcholinesterase (AChE-1) and form 2 acetylcholinesterase (AChE-2) structures of enzymes do not affect in any way (there is no regularity of change or significant deviations) the values of the binding energy (ΔGb) recorded in the AChE-OPs complexes. However, the mutations analyzed in AChE are associated with a structural modification that causes an inadequate interaction to complete the phosphorylation of the enzyme.

Root metabolic plasticity underlies functional diversity in mycorrhiza-enhanced stress tolerance in tomato.

Arbuscular mycorrhizal (AM) symbioses can improve plant tolerance to multiple stresses. We compared three AM fungi (AMF) from different genera, one of them isolated from a dry and saline environment, in terms of their ability to increase tomato tolerance to moderate or severe drought or salt stress. Plant physiological parameters and metabolic profiles were compared in order to find the molecular mechanisms underlying plant protection against stress. Mycorrhizal growth response was determined, and ultrahigh-performance LC-MS was used to compare the metabolic profile of plants under the different treatments. All AMF increased plant tolerance to stress, and the positive effects of the symbiosis were correlated with the severity of the stress. The AMF isolated from the stressful environment was the most effective in improving plant tolerance to salt stress. Differentially accumulated compounds were identified and the antistress properties of some of them were confirmed. We demonstrate that AM symbioses increase plant metabolic plasticity to cope with stress. Some responses were common to all AMF tested, while others were specifically related to particular isolates. Important metabolism reprograming was evidenced upon salt stress, and we identified metabolic pathways and compounds differentially accumulated in mycorrhizas that may underlie their enhanced tolerance to stress.

S-Dihydrodaidzein and 3-(1,3-benzoxazol-2-yl)-benzamide, Two New Potential ß-estrogen Receptor Ligands with Anti-adipogenic Activity.

BACKGROUND: The elucidation of molecular pathways associated with adipogenesis has evidenced the relevance of estrogen and estrogen receptor beta (ERß). The positive effects of ERß ligands on adipogenesis, energy expenditure, lipolysis, food intake, and weight loss, make ERß an attractive target for obesity control. From ligand-based virtual screening, molecular docking, and molecular dynamic simulations, six new likely ERß ligands (C1 to C6) have been reported with potential for pharmacological obesity treatment. OBJECTIVE: In this study, the effect of molecules C1-C6 on adipogenesis using the murine 3T3-L1 cell line was evaluated. METHODS: Cell viability was assessed by MTT assays. Lipid accumulation and gene expression were investigated by ORO staining and real-time quantitative RT-PCR experiments, respectively. RESULTS: Cell viability was not significantly affected by C1-C6 at concentrations up to 10 µM. Interestingly, treatment with 10 µM of C1 (S-Dihydrodaidzein) and C2 (3-(1,3-benzoxazol-2-yl)- benzamide) for 72 h inhibited adipocyte differentiation; moreover, ORO staining evidenced a reduced intracellular lipid accumulation (40% at day 7). Consistently, mRNA expression of the adipogenic markers, PPARγ and C/EBPα, was reduced by 50% and 82%, respectively, in the case of C1, and by 83% and 59%, in the case of C2. CONCLUSION: Altogether, these results show the two new potential ß-estrogen receptor ligands, C1 and C2, to exhibit anti-adipogenic activity. They could further be used as lead structures for the development of more efficient drugs for obesity control.

A Computational Approach Using α-Carbonic Anhydrase to Find Anti-Trypanosoma cruzi Agents.

BACKGROUND: Chagas disease has an ineffective drug treatment despite efforts made over the last four decades. The carbonic anhydrase of Trypanosoma cruzi (α-TcCA) has emerged as an interesting target for the design of new antiparasitic compounds due to its crucial role in parasite processes. OBJECTIVE: The aim of this study was to identify potential α-TcCA inhibitors with trypanocide activity. METHOD: A maximum common substructure (MCS) and molecular docking were used to carry out a ligand- and structure-based virtual screening of ZINC20 and MolPort databases. The compounds selected were evaluated in an in vitro model against the NINOA strain of Trypanosoma cruzi, and cytotoxicity was determined in a murine model of macrophage cells J774.2. RESULTS: Five sulfonamide derivatives (C7, C9, C14, C19, and C21) had the highest docking scores (-6.94 to -8.31 kcal/mol). They showed key residue interactions on the active site of the α-TcCA and good biopharmaceutical and pharmacokinetic properties. C7, C9, and C21 had half-maximal inhibitory concentration (IC50) values of 26, 61.6, and 49 µM, respectively, against NINOA strain epimastigotes of Trypanosoma cruzi. CONCLUSION: Compounds C7, C9, and C21 showed trypanocide activity; therefore, these results encourage the development of new trypanocidal agents based on their scaffold.

Molecular docking and dynamic simulations of quinoxaline 1,4-di-N-oxide as inhibitors for targets from Trypanosoma cruzi, Trichomonas vaginalis, and Fasciola hepatica.

CONTEXT: Quinoxaline 1,4-di-N-oxide is a scaffold with a wide array of biological activities, particularly its use to develop new antiparasitic agents. Recently, these compounds have been described as trypanothione reductase (TR), triosephosphate isomerase (TIM), and cathepsin-L (CatL) inhibitors from Trypanosoma cruzi, Trichomonas vaginalis, and Fasciola hepatica, respectively. METHODS: Therefore, the main objective of this work was to analyze quinoxaline 1,4-di-N-oxide derivatives of two databases (ZINC15 and PubChem) and literature by molecular docking, dynamic simulation and complemented by MMPBSA, and contact analysis of molecular dynamics' trajectory on the active site of the enzymes to know their potential effect inhibitory. Interestingly, compounds Lit_C777 and Zn_C38 show preference as potential TcTR inhibitors over HsGR, with favorable energy contributions from residues including Pro398 and Leu399 from Z-site, Glu467 from γ-Glu site, and His461, part of the catalytic triad. Compound Lit_C208 shows potential selective inhibition against TvTIM over HsTIM, with favorable energy contributions toward TvTIM catalytic dyad, but away from HsTIM catalytic dyad. Compound Lit_C388 was most stable in FhCatL with a higher calculated binding energy by MMPBSA analysis than HsCatL, though not interacting with catalytic dyad, holding favorable energy contribution from residues oriented at FhCatL catalytic dyad. Therefore, these kinds of compounds are good candidates to continue researching and confirming their activity through in vitro studies as new selective antiparasitic agents.

Ligand-Based and Structure-Based Virtual Screening of New Sodium Glucose Cotransporter Type 2 Inhibitors.

BACKGROUND: Diabetes mellitus is a metabolic disease that causes multiple complications and common comorbidities, which decreases the quality of life for people affected by the disease. Sodium glucose cotransporter type 2 (SGLT2) participates in the reabsorption of 90% of glucose in the kidneys; therefore, it is an attractive drug target for controlling blood glucose levels. OBJECTIVE: The aim in this work was to obtain new potential SGLT2 inhibitors. METHODS: A ligand-based virtual screening (LBVS) from the ZINC15, PubChem and ChemSpider databases using the maximum common substructure (MCS) scaffold was performed. RESULT: A total of 341 compounds were obtained and analyzed by molecular docking on the active site of SGLT2. Subsequently, 15 compounds were selected for molecular dynamics (MD) simulation analysis. The compounds derived of spiroketal Sa1, Sa4, and Sa9 (≤ 3.5 Å) in complex with the receptor SGLT2 showed good stability during 120 ns of MD. CONCLUSION: These compounds are proposed as potential SGLT2 inhibitors.

Experience with GyneFIX insertions in Spain: favorable acceptance of the intrauterine contraceptive implant with some limitations.

This study evaluates the incidents associated with GyneFIX insertion and first-year expulsion and continuity rates within the usual intrauterine contraceptive practice of a working group of Spanish professionals (GESEG), formed specifically with this aim. It is a prospective, multicenter, observational study of GyneFIX insertion in 1684 women. Data were prospectively collected on a structured form and processed centrally. Interest was focused on difficulties encountered during the insertion procedure and symptoms experienced during insertion. All terms were defined by consensus. Among the total, 18.6% of the women were nulliparous. GyneFIX insertion was rated easy in 92%, with more difficulty in nulliparous women, who showed significantly more symptoms during insertion of the device. First-year expulsion and continuity rates were 5.6 and 88 per 100 women, respectively. The pregnancy rate was 0.3 per 100 women/years. The GyneFIX system is an interesting alternative to standard IUDs for intrauterine contraception with copper, particularly in women who have experienced expulsion of other types of IUDs. Experienced professionals in IUD insertion quickly acquire familiarity with the GyneFIX insertion system, but proper implantation does not completely eliminate the risk of expulsion. Thus, the insertion system should be further modified to achieve a simpler, safer technique.