Insights of potential trypanocidal effect of the synthetic derivative (2E)-1-(4-aminophenyl)-3-(2,4-dichlorophenyl)prop-2-en-1-one: in vitro assay, MEV analysis, quantum study, molecular docking, molecular dynamics, MPO analysis, and predictive ADMET.

This study aims to evaluate the antitrypanosomiasis activity of a synthetic dichloro-substituted aminochalcone via in vitro assays against infected cell cultures, as well as a theoretical characterization of pharmacokinetics and pharmacodynamics against the protein targets of the evolutionary cycle of T. cruzi. The in vitro evaluation of parasite proliferation inhibition was performed via cytotoxicity analysis on mammalian host cells, effect on epimastigote and trypomastigote forms, and cell death analysis, while computer simulations characterized the electronic structure of (2E)-1-(4-aminophenyl)-3-(2,4-dichlorophenyl)prop-2-en-1-one (DCl), the mechanism of action against the proteins of the evolutionary cycle of T. cruzi: Cruzain, Trypanothione reductase, TcGAPDH, and CYP51 by molecular docking and dynamics and predictive pharmacokinetics by MPO-based ADMET. The in vitro tests showed that the DCl LC50 in order of 178.9 ± 23.9 was similar to the BZN, evidencing the effectiveness of chalcone against Trypomastigotes. Molecular docking and dynamics simulations suggest that DCl acts on the active site of the CYP51 receptor, with hydrogen interactions that showed a high degree of occupation, establishing a stable complex with the target. MPO analysis and ADMET prediction tests suggest that the compound presents an alignment between permeability and hepatic clearance, although it presents low metabolic stability. Chalcone showed stable pharmacodynamics against the CYP51 target, but can form reactive metabolites from N-conjugation and C = C epoxidation, as an indication of controlled oral dose, although the estimated LD50 rate > 500 mg/kg is a indicative of low incidence of lethality by ingestion, constituting a promising therapeutic strategy.

Structure-based virtual screening of mangiferin derivatives with antidiabetic action: a molecular docking and dynamics study and MPO-based drug-likeness approach.

Extracts from Mangifera indica leaves and its main component, mangiferin, have proven antidiabetic activity. In this study, mangiferin and its natural derivatives Homomangiferin (HMF), Isomangiferin (IMF), Neomangiferin (NMF), Glucomangiferin (GMF), Mangiferin 6'-gallate (MFG), and Norathyriol (NRT) were compared regarding their action on Diabetes mellitus (DM), employing docking and molecular dynamics (MD) simulations to analyze interactions with the aldose reductase enzyme, the precursor to the conversion of glucose into sorbitol. Notably, HMF showed significant affinity to residues in the active site of the enzyme, including Trp 79, His 110, Trp 111, Phe 122, and Phe 300, with an energy of - 7.2 kcal/mol, observed in the molecular docking simulations. MD reinforced the formation of stable complexes for HMF and MFG with the aldose reductase, with interaction potential energies (IPE) in the order of - 300.812 ± 52 kJ/mol and - 304.812 ± 52 kJ/mol, respectively. The drug-likeness assessment, by multiparameter optimization (MPO), highlighted that HMF and IMF have similarities with polyphenols and glycosidic flavonoids recently patented as antidiabetics, revealing that high polarity (TPSA > 180 Å2) is a favorable property for subcutaneous administration, especially because of the gradual passive cell permeability values in biological tissues, with Papp values estimated at < 10 × 10-6 cm/s. These compounds are metabolically stable against metabolic enzymes, resulting in a low toxic incidence by metabolic activation, corroborating with a lethal dose (LD50) greater than 2000 mg/kg. In this way, HMF showed a systematic alignment between predicted pharmacokinetics and pharmacodynamics, characterizing it as the most favorable substance for inhibiting aldose reductase. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-03978-9.

In Silico Study in MPO and Molecular Docking of the Synthetic Drynaran Analogues Against the Chronic Tinnitus: Modulation of the M1 Muscarinic Acetylcholine Receptor.

Tinnitus is a syndrome that affects the human auditory system and is characterized by a perception of sounds in the absence of acoustic stimuli, or in total silence. Research indicates that muscarinic acetylcholine receptors (mAChRs), especially the M1 type, have a fundamental role in the alterations of auditory perceptions of tinnitus. Here, a series of computer-aided tools were used, from molecular surface analysis software to services available on the web for estimating pharmacokinetics and pharmacodynamics. The results infer that the low lipophilicity ligands, that is, the 1a-d alkyl furans, present the best pharmacokinetic profile, as compounds with an optimal alignment between permeability and clearance. However, only ligands 1a and 1b have properties that are safe for the central nervous system, the site of cholinergic modulation. These ligands showed similarity with compounds deposited in the European Molecular Biology Laboratory chemical (ChEMBL) database acting on the mAChRs M1 type, the target selected for the molecular docking test. The simulations suggest that the 1 g ligand can form the ligand-receptor complex with the best affinity energy order and that, together with the 1b ligand, they are competitive agonists in relation to the antagonist Tiotropium, in addition to acting in synergism with the drug Bromazepam in the treatment of chronic tinnitus.

De novo design of bioactive phenol and chromone derivatives for inhibitors of Spike glycoprotein of SARS-CoV-2 in silico.

This work presents the synthesis of 12 phenol and chromone derivatives, prepared by the analogs, and the possibility of conducting an in silico study of its derivatives as a therapeutic alternative to combat the SARS-CoV-2, pathogen responsible for COVID-19 pandemic, using its S-glycoprotein as a macromolecular target. After the initial screening for the ranking of the products, it was chosen which structure presented the best energy bond with the target. As a result, derivative 4 was submitted to a molecular growth study using artificial intelligence, where 8436 initial structures were obtained that passed through the interaction filters and similarity to the active glycoprotein pocket through the MolAICal computational package. Thus, 557 Hits with active configuration were generated, which is very promising compared to the BLA reference link for inhibiting the biological target. Molecular dynamics also simulated these compounds to verify their stability within the active protein site to seek new therapeutic propositions to fight against the pandemic. The Hit 48 and 250 are the most active compounds against SARS-CoV-2. In summary, the results show that the Hit 250 would be more active than the natural compound, which could be further developed for further testing against SARS-CoV-2. The study employs the de novo approach to design new drugs, combining artificial intelligence and molecular dynamics simulations to create efficient molecular structures. This research aims to contribute to the development of effective therapeutic strategies against the pandemic.

Heterocyclic chalcone (E)-1-(2-hydroxy-3,4,6-trimethoxyphenyl)-3-(thiophen-2-yl) prop-2-en-1-one derived from a natural product with antinociceptive, anti-inflammatory, and hypoglycemic effect in adult zebrafish.

Diabetes is a disease linked to pathologies, such as chronic inflammation, neuropathy, and pain. The synthesis by the Claisen-Schmidt condensation reaction aims to obtain medium to high yield chalconic derivatives. Studies for the synthesis of new chalcone molecules aim at the structural manipulation of aromatic rings, as well as the replacement of rings by heterocycles, and combination through chemical reactions of synthesized structures with other molecules, in order to enhance biological activity. A chalcone was synthesized and evaluated for its antinociceptive, anti-inflammatory and hypoglycemic effect in adult zebrafish. In addition to reducing nociceptive behavior, chalcone (40 mg/kg) reversed post-treatment-induced acute and chronic hyperglycemia and reduced carrageenan-induced abdominal edema in zebrafish. It also showed an inhibitory effect on NO production in J774A.1 cells. When compared with the control groups, the oxidative stress generated after chronic hyperglycemia and after induction of abdominal edema was significantly reduced by chalcone. Molecular docking simulations of chalcone with Cox -1, Cox-2, and TRPA1 channel enzymes were performed and indicated that chalcone has a higher affinity for the COX-1 enzyme and 4 interactions with the TRPA1 channel. Chalcone also showed good pharmacokinetic properties as assessed by ADMET. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03696-8.

GABAA and serotonergic receptors participation in anxiolytic effect of chalcones in adult zebrafish.

The prevalence of anxiety is a significant public health problem, being the 24th leading cause of disability in individuals affected by this disorder. In this context, chalcones, a flavonoid subclass obtained from natural or synthetic sources, interact with central nervous system (CNS) receptors at the same binding site as benzodiazepines, the primary drugs used in the treatment of anxiety. Thus, our study investigates the anxiolytic effect of synthetic chalcones derived from the natural product 2-hydroxy-3,4,6-trimethoxyacetophenone isolated from Croton anisodontus Müll.Arg. in modulating anxiolytic activity via GABAergic and serotoninergic neurotransmission in an adult zebrafish model. Chalcones 1 and 2 were non-toxic to adult zebrafish and showed anxiolytic activity via GABAA receptors. Chalcone 2 also had its anxiolytic action reversed by the antagonist granisetron, indicating the participation of serotonergic receptors 5HTR3A/3B in the anxiolytic effect. In addition, molecular docking results showed that chalcones have a higher affinity for the GABAA receptor than DZP and binding in the same region of the DZP binding site, indicating a similar effect to the drug. Furthermore, the interaction of chalcones with GABAA and 5-HT3A receptors demonstrates the anxiolytic effect potential of these molecules.Communicated by Ramaswamy H. Sarma.

Naphthoquinones biflorin and bis-biflorin (Capraria biflora) as possible inhibitors of the fungus Candida auris polymerase: molecular docking, molecular dynamics, MM/GBSA calculations and in silico drug-likeness study.

A new worldwide concern has emerged with the recent emergence of infections caused by Candida auris. This reflects its comparative ease of transmission, substantial mortality, and the increasing level of resistance seen in the three major classes of antifungal drugs. Efforts to create a better design for structure-based drugs that described numerous modifications and the search for secondary metabolic structures derived from plant species are likely to reduce the virulence of several fungal pathogens. In this context, the present work aimed to evaluate in silico two naphthoquinones isolated from the roots of Capraria biflora, biflorin, and its dimmer, bis-biflorin, as potential inhibitors of Candida auris polymerase. Based on the simulation performed with the two naphthoquinones, biflorin and bis-biflorin, it can be stated that bis-biflorin showed the best interactions with Candida auris polymerase. Still, biflorin also demonstrated favorable coupling energy. Predictive pharmacokinetic assays suggest that biflorin has high oral bioavailability and more excellent metabolic stability compared to the bis-biflorin analogue. constituting a promising pharmacological tool.Communicated by Ramaswamy H. Sarma.

Hypoglycemic and hepatoprotective effects in adult zebrafish (Danio rerio) of fisetinidol isolated from Bauhinia pentandra: In vivo and in silico assays.

Diabetes mellitus is a chronic metabolic disorder that has been increasing drastically around the worldwide. It is important to emphasize that although many drugs are commercially available to treat diabetes, many of them have shown a number of adverse effects. Therefore, search for new antidiabetic agents is of great interest, and natural products, especially those obtained from plants sources, may be an alternative to available drugs. This study reports the in vivo and in silico evaluation of the hypoglycemic activity of fisetinidol. The conformational analysis confirmed that the fisetinidol compound possesses two valleys in the potential energy curve, showing a stable conformer on the global minimum of the PES defined by the dihedral angle θ (C6-C7-O-H) at 179.9°, whose energy is equal to zero. In addition, fisetinidol has shown promise in glycemic control and oxidative stress caused by hyperglycemia induced by high sucrose concentration, causing hypoglycemic and hepatoprotective effects in adult zebrafish. ADMET studies showed that fisetinidol has high passive permeability, low clearance and low toxic risk by ingestion, and computational studies demonstrated that fisetinidol complexes in the same region as metformin and α-acarbose, which constitutes a strong indication that fisetinidol has the same inhibitory mechanisms of α-acarbose and metformin.Communicated by Ramaswamy H. Sarma.

HIF1 inhibition of the biflavonoids against pancreas cancer: drug-likeness, bioavailability, ADMET, PASS, molecular docking, molecular dynamics, and MM/GBSA calculations.

Pancreatic cancer is an aggressive disease with a high death rate and is difficult to treat. This disease, in the most cases, is asymptomatic until it progresses to an advanced stage. Therefore, the search for bioactive molecules is urgent to combat pancreatic cancer. Then, this work analyzed the interaction potential of agathisflavone and amentoflavone molecules against the HIF1 target using the ADMET, molecular docking, and molecular dynamics simulations. More recent drug-likeness filters that combine physicochemical and physiological parameters have shown that high polar surface area (TPSA > 75 Å2) drives biflavonoids out of the toxic drug space of Pfizer dataset. Regarding the pharmacokinetic descriptors, it was possible to notice that Amentoflavone showed a better order of passive cell permeability (Papp = 8 × 10-6 cm/s) and better metabolic stability, biotransformed by aromatic hydroxylation reactions by the CYP3A4 isoenzyme on the human liver, that favor its hepatic clearance. The molecular docking and molecular dynamics simulations indicated the high interaction potential and stability between the ligands analyzed (highlighted the amentoflavone molecule), respectively. The MM/GBSA calculations showed that the amentoflavone ligand registered the highest ΔG binding value of -32.6957 kcal/mol with the HIF1 target. Then, this molecule may be used as a potential inhibitor of pancreatic cancer. In this perspective, the present work represents an initial step in the virtual bioprospecting a pharmacological tool for treating of pancreatic cancer.Communicated by Ramaswamy H. Sarma.

Antichagasic evaluation, molecular docking and ADMET properties of the chalcone (2E)-3-(2-fluorophenyl)-1-(2-hydroxy- 3,4,6-trimethoxyphenyl)prop-2-en-1-one against Trypanosoma cruzi.

Characterized as a neglected disease, Chagas disease is an infection that, in the current scenario, affects about 8 million people per year, with a higher incidence in underdeveloped countries, Chagas is responsible for physiological disabilities that result in impacts that are slightly reflected in world socioeconomic stability. Although treatments are based on drugs such as Benznidazole, the pathology lacks a continuous treatment method with low toxicological incidence. The present study estimates the anti-chagasic activity of the synthetic chalcone CPN2F based on the alignment between in vitro tests and structural classification in silico studies, molecular docking and ADMET studies. The in vitro tests showed a reduction in the protozoan metabolism in host cells (LLC-MK2). At the same time, the molecular docking models evaluate this growth inhibition through the synergistic effect associated with Benznida- zole against validated therapeutic target key stages (Cruzaine TcGAPDH and Trypanothione reductase) of the Trypanosoma cruzi development cycle. The in silico prediction results reveal an alignment between pharmacokinetic attributes, such as renal absorption and release, which allow the preparation of CPN2F as an antichagasic drug with a low incidence of organic toxicity.Communicated by Ramaswamy H. Sarma.

Diterpene Sonderianin isolated from Croton blanchetianus exhibits acetylcholinesterase inhibitory action and anxiolytic effect in adult zebrafish (Danio rerio) by 5-HT system.

Croton blanchetianus is known as 'marmeleiro preto', a very widespread shrub in Northeast Brazil. Terpenoids, steroids and phenolic compounds are among the reported secondary metabolites of the Croton genus that are a potential source of bioactive compounds. This study evaluated the anxiolytic potential of clerodine-type diterpene, sonderianin (CBWS) isolated from the stem bark of C. blanchetianus and its mechanism of action in adult zebrafish (Danio rerio) (ZFa). The anticonvulsant and anti-acetylcholinesterase effects have also been explored. ZFa (n = 6/group) were treated intraperitoneally (ip; 20 µL) with CBWS (4, 12 and 40 mg/kg) and vehicle (3% DMSO; 20 µL) and subjected to locomotor activity tests, as well as toxicity acute 96 h. CBWS was also administered for analysis in the light/dark test. The involvement of the serotonergic system (5-HT) was investigated using 5-HTR1, 5-HTR2A/2C and 5-HTR3A/3B receptor antagonists. Anxiolytic doses were tested for pentylenetetrazol-induced seizure in ZFa. The inhibitory activity of the enzyme acetylcholinesterase (AChE) was measured. CBWS was not considered toxic and reduced locomotor activity. The results of the present study identified for the first time the interaction of the diterpene sonderianina in the CNS. This study provides evidence that CBWS has an anxiolytic effect mediated by serotonergic (5-HT) involvement and anti-acetylcholinesterase action. The 5-HTR1 and 5-HTR2A/2C receptors may be implicated in the low anticonvulsant effect in CBWS.Communicated by Ramaswamy H. Sarma.

Computational approach towards the design of artemisinin-thymoquinone hybrids against main protease of SARS-COV-2.

BACKGROUND: The sanitary emergency installed in the world, generated by the pandemic of COVID-19, instigates the search for scientific strategies to mitigate the damage caused by the disease to different sectors of society. The disease caused by the coronavirus, SARS-CoV-2, reached 216 countries/territories, where about 199 million people were reported with the infection. Of these, more than 4 million died. In this sense, strategies involving the development of new antiviral molecules are extremely important. The main protease (Mpro) from SARS-CoV-2 is an important target, which has been widely studied for antiviral treatment. This work aims to perform a screening of pharmacodynamics and pharmacokinetics of synthetic hybrids from thymoquinone and artemisin (THY-ART) against COVID-19. RESULTS: Molecular docking studies indicated that hybrids of artemisinin and thymoquinone showed a relevant interaction with the active fraction of the enzyme Mpro, when compared to the reference drugs. Furthermore, hybrids show an improvement in the interaction of substances with the enzyme, mainly due to the higher frequency of interactions with the Thr199 residue. ADMET studies indicated that hybrids tend to permeate biological membranes, allowing good human intestinal absorption, with low partition to the central nervous system, potentiation for CYP-450 enzyme inhibitors, low risk of toxicity compared to commercially available drugs, considering mainly mutagenicity and cardiotoxicity, low capacity of hybrids to permeate the blood-brain barrier, high absorption and moderate permeability in Caco-2 cells. In addition, T1-T7 tend to have a better distribution of their available fractions to carry out diffusion and transport across cell membranes, as well as increase the energy of interaction with the SARS-CoV-2 target. CONCLUSIONS: Hybrid products of artemisinin and thymoquinone have the potential to inhibit Mpro, with desirable pharmacokinetic and toxicity characteristics compared to commercially available drugs, being indicated for preclinical and subsequent clinical studies against SARS-CoV-2. Emphasizing the possibility of synergistic use with currently used drugs in order to increase half-life and generate a possible synergistic effect. This work represents an important step for the development of specific drugs against COVID-19.