ABSTRACT
Four afatinib derivatives were designed and modeled. These derivatives were compared to the known tyrosine-kinase inhibitors in treating Chronic Myeloid Leukemia, i.e., imatinib and ponatinib. The molecules were evaluated through computational methods, including docking studies, the non-covalent interaction index, Electron Localization and Fukui Functions, in silico ADMET analysis, QTAIM, and Heat Map analysis. The AFA(IV) candidate significantly increases the score value compared to afatinib. Furthermore, AFA(IV) was shown to be relatively similar to the ponatinib profile when evaluating a range of molecular descriptors. The addition of a methylpiperazine ring seems to be well distributed in the structure of afatinib when targeting the BCR-ABL enzyme, providing an important hydrogen bond interaction with the Asp381 residue of the DFG-switch of BCR-ABL active site residue and the AFA(IV) new chemical entities. Finally, in silico toxicity predictions show a favorable index, with some molecules presenting the loss of the irritant properties associated with afatinib in theoretical predictions.
Subject(s)
Afatinib , Fusion Proteins, bcr-abl , Molecular Docking Simulation , Protein Kinase Inhibitors , Fusion Proteins, bcr-abl/antagonists & inhibitors , Fusion Proteins, bcr-abl/genetics , Fusion Proteins, bcr-abl/chemistry , Afatinib/chemistry , Afatinib/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Humans , Models, Molecular , Computer Simulation , Mutation , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Hydrogen Bonding , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Imidazoles/chemistry , Imidazoles/pharmacology , PyridazinesABSTRACT
Currently, pollution due to heavy metals, in particular dissolved mercury, is a major concern for society and the environment. This work aims to evaluate the current scenario regarding the removal/elimination of mercury. Mercury removal through adsorption is mainly done through artificial resins and metallic-organic frameworks. In the case of the zinc organic framework, it was able to adsorb Hg2+, reaching an adsorption capacity of 802 mg g-1. As for the Hg(0) the coconut husk was found to have the lowest equilibrium time, 30 min, and the highest adsorption capacity of 956.2 mg g-1. Experimental reports and molecular simulation indicate that the adsorption of mercury and other chemical forms occurs due to electrostatic interactions, ion exchange, precipitation, complexation, chelation, and covalent bonds, according to the material nature. The reported thermodynamic results show that, in most cases, the mercury adsorption has an endothermic nature with enthalpy levels below 40 kJ mol-1. Thermal and chemical regeneration methods lead to a similar number of 5 cycles for different materials. The presence of other ions, in particular cadmium, lead, and copper, generates an antagonistic effect for mercury adsorption. Regarding the other current technologies, it was found that mercury removal is feasible through precipitation, phytoremediation, and marine microalgae; all these methods require constant chemicals or a slow rate of removal according to the conditions. Advanced oxidative processes have noteworthy removal of Hg(0); however, Fenton processes lead to mineralization, which leads to Fe2+ and Fe3+ in solution; sonochemical processes are impossible to scale up at the current technology level; and electrochemical processes consume more energy and require constant changes of the anode and cathode. Overall, it is possible to conclude that the adsorption process remains a more friendly, economical, and greener process in comparison with other processes.
ABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Hymenaea eriogyne Benth (Fabaceae) is popularly known as "Jatobá". Despite its use in folk medicine to treat inflammatory disorders, there are no descriptions that show its anti-inflammatory potential. AIM OF THE STUDY: In this sense, this study aimed to evaluate the anti-inflammatory and antivenom action of bark and leaves extract of H. eriogyne. MATERIALS AND METHODS: The in vivo anti-inflammatory activity was conducted by carrageenan-induced paw edema and zymosan-induced air pouch models, evaluating the edematogenic effect, leukocyte migration, protein concentration, levels of pro-inflammatory cytokines, malondialdehyde (MDA) and myeloperoxidase (MPO) activity. The antivenom potential was investigated in vitro on the enzymatic action (proteolytic, phospholipase and hyaluronidase) of Bothrops brazili and B. leucurus venom, as well as in vivo on the paw edema model induced by B. leucurus. Furthermore, the influence of its markers (astilbin and rutin) on MPO activity was investigated in silico. For molecular docking, AutodockVina, Biovia Discovery Studio, and Chimera 1.16 software were used. RESULTS: The extracts and bark and leaves of H. eriogyne revealed a high anti-inflammatory effect, with a reduction in all inflammatory parameters evaluated. The bark extract showed superior results when compared to the leaf extract, suggesting the influence of the astilbin concentration, higher in the bark, on the anti-inflammatory action. In addition, only the H. eriogyne bark extract was able to reduce MDA, indicating an associated antioxidant effect. Regarding the in vitro antivenom action, the extracts (bark and leaves) revealed the ability to inhibit the proteolytic, phospholipase and hyaluronidase action of both bothropic venom, with a greater effect against B. leucurus venom. In vivo, extracts from the bark and leaves of H. eriogyne (50-200 mg/kg) showed antiedematogenic activity, reducing the release of MPO and pro-inflammatory cytokines, indicating the presence of bioactive components useful in controlling the inflammatory process induced by the venom. In the in silico assays, astilbin and rutin showed reversible interactions of 9 possible positions and orientations towards MPO, with affinities of -9.5 and -10.4 kcal/mol and interactions with Phe407, Gln91, His95 and Arg239, important active pockets of MPO. Rutin demonstrated more effective types of interactions with MPO. CONCLUSION: This approach reveals for the first time the anti-inflammatory action of H. eriogyne bark and leaf extracts in vivo, as well as its antiophidic potential. Moreover, the distinct effect of pharmacogens as antioxidant agents and distinct effect of astilbin and rutin under MPO sheds light on the different anti-inflammatory mechanisms of bioactive compounds present in H. eriogyne extracts, with high potential for the prospection of new pharmacological agents.
Subject(s)
Anti-Inflammatory Agents , Carrageenan , Edema , Molecular Docking Simulation , Plant Bark , Plant Extracts , Plant Leaves , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/isolation & purification , Animals , Plant Extracts/pharmacology , Plant Extracts/chemistry , Edema/drug therapy , Edema/chemically induced , Plant Leaves/chemistry , Plant Bark/chemistry , Male , Structure-Activity Relationship , Peroxidase/metabolism , Fabaceae/chemistry , Antivenins/pharmacology , Antivenins/chemistry , Rats, Wistar , Crotalid Venoms/toxicity , Mice , Bothrops , Cytokines/metabolism , Zymosan , Biomarkers/metabolism , Rutin/pharmacologyABSTRACT
CONTEXT: Although quantum mechanical calculations have proven effective in accurately predicting UV absorption and assessing the antioxidant potential of compounds, the utilization of computer-aided drug design (CADD) to support sustainable synthesis research of new sunscreen active ingredients remains an area with limited exploration. Furthermore, there are ongoing concerns about the safety and effectiveness of existing sunscreens. Therefore, it remains crucial to investigate photoprotection mechanisms and develop enhanced strategies for mitigating the harmful effects of UVR exposure, improving both the safety and efficacy of sunscreen products. A previous study conducted synthesis research on eight novel hybrid compounds (I-VIII) for use in sunscreen products by molecular hybridization of trans-resveratrol (RESV), avobenzone (AVO), and octinoxate (OMC). Herein, time-dependent density functional theory (TD-DFT) calculations performed in the gas phase on the isolated hybrid compounds (I-VIII) proved to reproduce the experimental UV absorption. Resveratrol-avobenzone structure-based hybrids (I-IV) present absorption maxima in the UVB range with slight differences between them, while resveratrol-OMC structure-based hybrids (V-VIII) showed main absorption in the UVA range. Among RESV-OMC hybrids, compounds V and VI exhibited higher UV absorption intensity, and compound VIII stood out for its broad-spectrum coverage in our simulations. Furthermore, both in silico and in vitro analyses revealed that compounds VII and VIII exhibited the highest antioxidant activity, with compound I emerging as the most reactive antioxidant within RESV-AVO hybrids. The study suggests a preference for the hydrogen atom transfer (HAT) mechanism over single-electron transfer followed by proton transfer (SET-PT) in the gas phase. With a strong focus on sustainability, this approach reduces costs and minimizes effluent production in synthesis research, promoting the eco-friendly development of new sunscreen active ingredients. METHODS: The SPARTAN'20 program was utilized for the geometry optimization and energy calculations of all compounds. Conformer distribution analysis was performed using the Merck molecular force field 94 (MMFF94), and geometry optimization was carried out using the parametric method 6 (PM6) followed by density functional theory (DFT/B3LYP/6-31G(d)). The antioxidant behavior of the hybrid compounds (I-VIII) was determined using the highest occupied molecular orbital (εHOMO) and the lowest unoccupied molecular orbital (εLUMO) energies, as well as the bond dissociation enthalpy (BDE), ionization potential (IP), and proton dissociation enthalpy (PDE) values, all calculated at the same level of structural optimization. TD-DFT study is carried out to calculate the excitation energy using the B3LYP functional with the 6-31G(d) basis set. The calculated transitions were convoluted with a Gaussian profile using the Gabedit program.
Subject(s)
Antioxidants , Computer-Aided Design , Drug Design , Resveratrol , Sunscreening Agents , Ultraviolet Rays , Sunscreening Agents/chemistry , Antioxidants/chemistry , Antioxidants/pharmacology , Resveratrol/chemistry , Propiophenones/chemistry , Density Functional Theory , Stilbenes/chemistry , Stilbenes/pharmacology , Models, Molecular , Quantum Theory , Molecular StructureABSTRACT
CONTEXT: Given the diverse pathophysiological mechanisms underlying Alzheimer's disease, it is improbable that a single targeted drug will prove successful as a therapeutic strategy. Therefore, exploring various hypotheses in drug design is imperative. The sequestration of Fe(II) and Zn(II) cations stands out as a crucial mechanism based on the mitigation of reactive oxygen species. Moreover, inhibiting acetylcholinesterase represents a pivotal strategy to enhance acetylcholine levels in the synaptic cleft. This research aims to investigate the analogs of Huperzine A, documented in scientific literature, considering of these two hypotheses. Consequently, the speciation chemistry of these structures with Fe(II) and Zn(II) was scrutinized using quantum chemistry calculations, molecular docking simulations, and theoretical predictions of pharmacokinetics properties. From the pharmacokinetic properties, only two analogs, HupA-A1 and HupA-A2, exhibited a theoretical permeability across the blood-brain barrier; on the other hand, from a thermodynamic standpoint, the enantiomers of HupA-A2 showed negligible chelation values. The enantiomers with the most favorable interaction parameters were S'R'HupA-A1 (ΔGBIND = -40.0 kcal mol-1, fitness score = 35.5) and R'R'HupA-A1 (ΔGBIND = -35.5 kcal mol-1, fitness score = 22.61), being compared with HupA (ΔGBIND = -41.75 kcal mol-1, fitness score = 39.95). From this study, some prime candidates for promising drug were S'R'HupA-A1 and R'R'HupA-A1, primarily owing to their favorable thermodynamic chelating capability and potential anticholinesterase mechanism. METHODS: Quantum chemistry calculations were carried out at B3LYP/6-31G(d) level, considering the IEF-PCM(UFF) implicit solvent model for water. The coordination compounds were assessed using the Gibbs free energy variation and hard and soft acid theory. Molecular docking calculations were conducted using the GOLD program, based on the crystal structure of the acetylcholinesterase protein (PDB code = 4EY5), where the ChemScore function was employed with the active site defined as the region within a 15-Å radius around the centroid coordinates (X = -9.557583, Y = -43.910473, Z = 31.466687). Pharmacokinetic properties were predicted using SwissADME, focusing on Lipinski's rule of five.
Subject(s)
Acetylcholinesterase , Alkaloids , Alzheimer Disease , Cholinesterase Inhibitors , Molecular Docking Simulation , Sesquiterpenes , Alzheimer Disease/drug therapy , Alkaloids/chemistry , Sesquiterpenes/chemistry , Humans , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Acetylcholinesterase/metabolism , Acetylcholinesterase/chemistry , Blood-Brain Barrier/metabolism , Thermodynamics , Zinc/chemistry , Models, Molecular , Iron/chemistry , Iron/metabolismABSTRACT
CONTEXT: The advancement in the development of second-generation drugs in the field of antihistamines represents a significant milestone in the management of allergic diseases, targeting the effects of histamine. The efficacy of bilastine in treating allergic disorders has sparked interest in investigating its polymorphism, a crucial property that impacts quality, safety, and effectiveness as per regulatory guidelines. This study examines the polymorphism of bilastine, focusing on two crystalline forms labeled as Form I and Form II. Utilizing advanced analytical techniques, the research explores the structural characteristics and molecular interactions within these forms. Geometric parameters, such as bond lengths, bond angles, and torsion angles, are examined to comprehend molecular conformations and crystal packing arrangements. Hydrogen bonding, covalent bonds, and van der Waals forces contribute to the unique supramolecular arrangements in these forms. This study provides a significant contribution to understanding bilastine's polymorphism, offering critical insights to researchers and regulatory bodies to ensure the quality, efficacy, and safety of antihistamine products. METHODS: The molecular conformation of two bilastine forms was obtained through DFT with the exchange-correlation functional M06-2X and the 6-311 + + G(d,p) basis set, and the results were compared with the experimental X-ray. The atomic coordinates were obtained directly from the crystalline structures, and charge transfer was also investigated using frontier molecular orbitals (HOMO and LUMO), and MEP map in order to evaluate the energies associated with charge transfers and regions of high electron affinity. The geometric and topological parameters and intermolecular interactions in the crystals were analyzed using Hirshfeld Surface.
ABSTRACT
Intelectins belong to a family of lectins with specific and transitory carbohydrate interaction capabilities. These interactions are related to the activity of agglutinating pathogens, as intelectins play a significant role in immunity. Despite the prominent immune defense function of intelectins, limited information about its structural characteristics and carbohydrate interaction properties is available. This study investigated an intelectin transcript identified in RNA-seq data obtained from the South American lungfish (Lepidosiren paradoxa), namely LpITLN2-B. The structural analyses predicted LpITLN2-B to be a homo-trimeric globular protein with the fibrinogen-like functional domain (FReD), exhibiting a molecular mass of 57 kDa. The quaternary structure is subdivided into three monomers, A, B, and C, and each domain comprises 11 ß-sheets: an anti-parallel ß-sheet, a ß-hairpin, and a disordered ß-sheet structure. Molecular docking demonstrates a significant interaction with disaccharides rather than monosaccharides. The preferential interaction with disaccharides highlights the potential interaction with pathogen molecules, such as LPS and Poly(I:C). The hemagglutination assay inhibited lectins activity, especially maltose and sucrose, highlighting lectin activity in L. paradoxa samples. Overall, our results show the potential relevance of LpITLN2-B in L. paradoxa immune defense against pathogens.
Subject(s)
Fish Proteins , Fishes , Immunity, Innate , Lectins , Animals , Lectins/chemistry , Lectins/metabolism , Lectins/immunology , Lectins/genetics , Fishes/immunology , Fishes/genetics , Fish Proteins/genetics , Fish Proteins/chemistry , Fish Proteins/immunology , Fish Proteins/metabolism , Molecular Docking Simulation , Amino Acid Sequence , GPI-Linked Proteins/chemistry , GPI-Linked Proteins/metabolism , GPI-Linked Proteins/genetics , GPI-Linked Proteins/immunologyABSTRACT
The increase in multi-drug resistant Candida strains has caused a sharp rise in life-threatening fungal infections in immunosuppressed patients, including those with SARS-CoV-2. Novel antifungal drugs are needed to combat multi-drug-resistant yeasts. This study aimed to synthesize a new series of 2-oxazolines and evaluate the ligands in vitro for the inhibition of six Candida species and in silico for affinity to the CYP51 enzymes (obtained with molecular modeling and protein homology) of the same species. The 5-(1,3-diphenyl-1H-pyrazol-4-yl)-4-tosyl-4,5-dihydrooxazoles 6a-j were synthesized using the Van Leusen reaction between 1,3-diphenyl-4-formylpyrazoles 4a-j and TosMIC 5 in the presence of K2CO3 or KOH without heating, resulting in short reaction times, high compound purity, and high yields. The docking studies revealed good affinity for the active site of the CYP51 enzymes of the Candida species in the following order: 6a-j > 4a-j > fluconazole (the reference drug). The in vitro testing of the compounds against the Candida species showed lower MIC values for 6a-j than 4a-j, and for 4a-j than fluconazole, thus correlating well with the in silico findings. According to growth rescue assays, 6a-j and 4a-j (like fluconazole) inhibit ergosterol synthesis. The in silico toxicity assessment evidenced the safety of compounds 6a-j, which merit further research as possible antifungal drugs.
Subject(s)
Antifungal Agents , Candida , Microbial Sensitivity Tests , Molecular Docking Simulation , Antifungal Agents/pharmacology , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Candida/drug effects , Humans , Oxazoles/chemistry , Oxazoles/pharmacology , Oxazoles/chemical synthesis , Pyrazoles/pharmacology , Pyrazoles/chemistry , Pyrazoles/chemical synthesis , Computer Simulation , SARS-CoV-2/drug effectsABSTRACT
L-Acetylcarnitine (ALC), a versatile compound, has demonstrated beneficial effects in depression, Alzheimer's disease, cognitive impairment, and other conditions. This study focuses on its antithyroid activity. The precursor molecule, L-carnitine, inhibited the uptake of triiodothyronine (T3) and thyroxine (T4), and it is possible that ALC may reduce the iodination process of T3 and T4. Currently, antithyroid drugs are used to control the excessive production of thyroid hormones (TH) through various mechanisms: (i) forming electron donor-acceptor complexes with molecular iodine, (ii) eliminating hydrogen peroxide, and (iii) inhibiting the enzyme thyroid peroxidase. To understand the pharmacological properties of ALC, we investigated its plausible mechanisms of action. ALC demonstrated the ability to capture iodine (Kc = 8.07 ± 0.32 x 105 M-1), inhibit the enzyme lactoperoxidase (LPO) (IC50 = 17.60 ± 0.76 µM), and scavenge H2O2 (39.82 ± 0.67 mM). A comprehensive physicochemical characterization of ALC was performed using FTIR, Raman, and UV-Vis spectroscopy, along with theoretical DFT calculations. The inhibition process was assessed through fluorescence spectroscopy and vibrational analysis. Docking and molecular dynamics simulations were carried out to predict the binding mode of ALC to LPO and to gain a better understanding into the inhibition process. Furthermore, albumin binding experiments were also conducted. These findings highlight the potential of ALC as a therapeutic agent, providing valuable insights for further investigating its role in the treatment of thyroid disorders.
Subject(s)
Iodine , Thyroid Gland , Lactoperoxidase/metabolism , Lactoperoxidase/pharmacology , Acetylcarnitine/metabolism , Acetylcarnitine/pharmacology , Hydrogen Peroxide/pharmacology , Iodine/chemistry , Models, TheoreticalABSTRACT
Giardiasis is a parasitosis caused by Giardia lamblia with significant epidemiological and clinical importance due to its high prevalence and pathogenicity. The lack of optimal therapies for treating this parasite makes the development of new effective chemical entities an urgent need. In the search for new inhibitors of the adenylyl cyclase gNC1 obtained from G. lamblia, 14 extracts from Argentinian native plants were screened. Lepechinia floribunda and L. meyenii extracts exhibited the highest gNC1 inhibitory activity, with IC50 values of 9 and 31 µg/mL, respectively. In silico studies showed rosmarinic acid, a hydroxycinnamic acid present in both mentioned species, to be a promising anti-gNC1 compound. This result was confirmed experimentally, with rosmarinic acid showing an IC50 value of 10.1 µM. Theoretical and experimental findings elucidate the molecular-level mechanism of rosmarinic acid, pinpointing the key interactions stabilizing the compound-enzyme complex and the binding site. These results strongly support that rosmarinic acid is a promising scaffold for developing novel compounds with inhibitory activity against gNC1, which could serve as potential therapeutic agents to treat giardiasis.
ABSTRACT
Seven 3-styrylcoumarins were tested for antileishmanial activity against Leishmania (Viannia) panamensis amastigotes. Cytotoxic activity was also evaluated against mammalian U-937 cells. The 3-methoxy-4-hydroxy coumarin derivative 6 was the most active with an IC50 of 40.5 µM, and did not reveal any conspicuous toxicity toward mammalian U-937 cells. Therefore, it may have potential to be considered as candidate for antileishmanial drug development. Further, among several druggable Leishmania targets, molecular docking studies revealed that compound 6 had docking preference by the N-myristoyltransferase (Lp-NMT) of Leishmania panamensis, showing a higher docking score of - 10.1 kcal mol-1 than positive controls and making this protein as a presumably druggable target for this compound. On the other hand, molecular dynamics simulations affirm the docking hypothesis, showing a conformational stability of the 6/Lp-NMT complex throughout 100 ns simulation. Moreover, the molecular mechanics/Poisson-Boltzmann surface area method also support the docking findings, revealing a total free energy of binding of - 47.26 ± 0.08 kcal mol-1, and identifying through energy decomposition analysis that those key aminoacids are contributing strongly to ligand binding. Finally, an optimal pharmacokinetic profile was also estimated for 6. Altogether, coumarin 6 could be addressed as starting point for further pharmacological studies concerning the therapeutic leishmaniasis intervention.
ABSTRACT
BACKGROUND: Neglected tropical diseases (NTDs) are parasitic and bacterial diseases that affect approximately 149 countries, mainly the poor population without basic sanitation. Among these, African Human Trypanosomiasis (HAT), known as sleeping sickness, shows alarming data, with treatment based on suramin and pentamidine in the initial phase and melarsoprol and eflornithine in the chronic phase. Thus, to discover new drugs, several studies point to rhodesain as a promising drug target due to the function of protein degradation and intracellular transport of proteins between the insect and host cells and is present in all cycle phases of the parasite. METHODOLOGY: Here, based on the previous studies by Nascimento et al. (2021) that show the main rhodesain inhibitors development in the last decade, molecular docking and dynamics were applied in these inhibitors datasets to reveal crucial information that can be into drug design. Thus, conventional and covalent docking was employed and highlighted the presence of Michael acceptors in the ligands in a peptidomimetics scaffold, and interaction with Gly19, Gly23, Gly65, Asp161, and Trp184 is essential to the inhibiting activity. RESULTS: Also, our findings using MD simulations and MM-PBSA calculations confirmed Gly19, Gly23, Gly65, Asp161, and Trp184, showing high binding energy (ΔGbind between -72.782 to -124.477 kJ.mol-1). In addition, Van der Waals interactions have a better contribution (-140,930 to -96,988 kJ.mol-1) than electrostatic forces (-43,270 to -6,854 kJ.mol-1), indicating Van der Waals interactions are the leading forces in forming and maintaining ligand-rhodesain complexes. CONCLUSION: Furthermore, the Dynamic Cross-Correlation Maps (DCCM) show more correlated movements for all complexes than the free rhodesain and strong interactions in the regions of the aforementioned residues. Principal Component Analysis (PCA) demonstrates complex stability corroborating with RMSF and RMSD. This study can provide valuable insights that can guide researchers worldwide to discover a new promising drug against HAT.
ABSTRACT
We report here the virtual screening design, synthesis and activity of eight new inhibitors of SphK1. For this study we used a pre-trained Graph Convolutional Network (GCN) combined with docking calculations. This exploratory analysis proposed nine compounds from which eight displayed significant inhibitory effect against sphingosine kinase 1 (SphK1) demonstrating a high level of efficacy for this approach. Four of these compounds also displayed anticancer activity against different tumor cell lines, and three of them (5), (6) and (7) have shown a wide inhibitory action against many of the cancer cell line tested, with GI50 below 5 µM, being (5) the most promising with TGI below 10 µM for the half of cell lines. Our results suggest that the three most promising compounds reported here are the pyrimidine-quinolone hybrids (1) and (6) linked by p-aminophenylsulfanyl and o-aminophenol fragments respectively, and (8) without such aryl linker. We also performed an exhaustive study about the molecular interactions that stabilize the different ligands at the binding site of SphK1. This molecular modeling analysis was carried out by using combined techniques: docking calculations, MD simulations and QTAIM analysis. In this study we also included PF543, as reference compound, in order to better understand the molecular behavior of these ligands at the binding site of SphK1.These results provide useful information for the design of new inhibitors of SphK1 possessing these structural scaffolds.
Subject(s)
Antineoplastic Agents , Phosphotransferases (Alcohol Group Acceptor) , Quinolones , Quinolones/pharmacology , Protein Kinase Inhibitors , Antineoplastic Agents/chemistry , Models, Molecular , Cell Line, Tumor , Molecular Docking Simulation , Drug Screening Assays, Antitumor , Cell Proliferation , Structure-Activity Relationship , Molecular StructureABSTRACT
CONTEXT AND RESULTS: Flavivirus diseases' cycles, especially Dengue and Yellow Fever, can be observed all over Brazilian territory, representing a great health concern. Additionally, there are no drugs available in therapy. In this scenario, in silico methodologies were applied to obtain physicochemical properties, as well as to better understand the ligand-biological target interaction mode of 20 previously reported NS2B/NS3 protease inhibitors of Dengue virus. Since catalytic site of flavivirus hold similarities, such as the same catalytic triad (His51, Asp75 e Ser135), the ability of this series of molecules to fit in Zika NS3 domains can be achieved. We performed an exploratory data analysis, using statistical methodologies, such as PCA (Principal Component Analysis) and HCA (Hierarchical Component Analysis), to assist the comprehension of how physicochemical properties impact the interaction observed by the docking studies, as well as to build a correlation between the respective ranked characteristics. Based on these previous studies, peptides were selected for the dynamics simulations, which were useful to better understand the ligand-protein interactions. Information relating to, for instance, energy, ΔG, average number of hydrogen bonds and distance from Ser135 (one of the main amino acids in the catalytic pocket) were discussed. In this sense, peptides 15 (considering ΔG value and Hbond number), 7 (ΔG and energy) and 1, 6, 7 and 15 (the proximity to Ser135 throughout the dynamics simulation) were highlighted as promising. Those interesting results could contribute to future studies regarding Zika virus drug design, since this infection represents a great concern in neglected populations. METHODS: The models were constructed in the ChemDraw software. The ligand parametrization was performed in the CHEM3D 17.0, UCSF Chimera. Docking simulations were carried out in the GOLD software, after the redocking validation. We used ASP as the function score. Additionally, for dynamics simulations we applied GROMACS software, exploring, mainly, free binding energy calculations. Exploratory analysis was carried out in Minitab 17.3.1 statistical software. Prior to the exploratory analysis, data of quantum chemical properties of the peptides were collected in Microsoft Excel spreadsheet and organized to obtain Hierarchical Cluster Analysis (HCA) and Principal Component Analysis (PCA).
Subject(s)
Zika Virus Infection , Zika Virus , Humans , Ligands , Peptides/pharmacology , Serine Endopeptidases , Amino AcidsABSTRACT
Human ß3-adrenoceptor (ß3AR) agonists were considered potential agents for the treatment of metabolic disorders. However, compounds tested as ß3AR ligands have shown marked differences in pharmacological profile in rodent and human species, although these compounds remain attractive as they were successfully repurposed for the therapy of urinary incontinence. In this work, some biarylamine compounds were designed and tested in silico as potential ß3AR agonists on 3-D models of mouse or human ß3ARs. Based on the theoretical results, we identified, synthesized and tested a biarylamine compound (polibegron). In CHO-K1 cells expressing the human ß3AR, polibegron and the ß3AR agonist BRL 37344 were partial agonists for stimulating cAMP accumulation (50 and 57% of the response to isoproterenol, respectively). The potency of polibegron was 1.71- and 4.5-fold higher than that of isoproterenol and BRL37344, respectively. These results indicate that polibegron acts as a potent, but partial, agonist at human ß3ARs. In C57BL/6N mice with obesity induced by a high-fat diet, similar effects of the equimolar intraperitoneal administration of polibegron and BRL37344 were observed on weight, visceral fat and plasma levels of glucose, cholesterol and triglycerides. Similarities and differences between species related to ligand-receptor interactions can be useful for drug designing.
Subject(s)
Adrenergic beta-Agonists , Receptors, Adrenergic, beta-3 , Cricetinae , Humans , Mice , Animals , Isoproterenol , Receptors, Adrenergic, beta-3/metabolism , Mice, Inbred C57BL , CHO Cells , Cricetulus , Adrenergic beta-Agonists/pharmacologyABSTRACT
Aim: This work aimed to investigate the antiviral activity of two 1,4-disubstituted-1,2,3-triazole derivatives (1 and 2) against Chikungunya virus (CHIKV) replication. Materials & methods: Cytotoxicity was analyzed using colorimetric assays and the antiviral potential was evaluated using plaque assays and computational tools. Results: Compound 2 showed antiviral activity against CHIKV 181-25 in BHK-21 and Vero cells. Also, this compound presented a higher activity against CHIKV BRA/RJ/18 in Vero cells, like compound 1. Compound 2 exhibited virucidal activity and inhibited virus entry while compound 1 inhibited virus release. Molecular docking suggested that these derivatives inhibit nsP1 protein while compound 1 may also target capsid protein. Conclusion: Both compounds exhibit promising antiviral activity against CHIKV by blocking different steps of virus replication.
ABSTRACT
Background: The impact of schistosomiasis, which affects over 230 million people, emphasizes the urgency of developing new antischistosomal drugs. Artificial intelligence is vital in accelerating the drug discovery process. Methodology & results: We developed classification and regression machine learning models to predict the schistosomicidal activity of compounds not experimentally tested. The prioritized compounds were tested on schistosomula and adult stages of Schistosoma mansoni. Four compounds demonstrated significant activity against schistosomula, with 50% effective concentration values ranging from 9.8 to 32.5 µM, while exhibiting no toxicity in animal and human cell lines. Conclusion: These findings represent a significant step forward in the discovery of antischistosomal drugs. Further optimization of these active compounds can pave the way for their progression into preclinical studies.
Subject(s)
Schistosomiasis , Schistosomicides , Animals , Humans , Schistosoma mansoni , Artificial Intelligence , Schistosomicides/pharmacology , Schistosomiasis/drug therapy , Drug DiscoveryABSTRACT
Cancer still represents a serious public health problem and one of the main problems related to the worsening of this disease is the ability of some tumors to develop metastasis. In this work, we synthesized a new series of chalcones and isoxazoles derived from eugenol and analogues as molecular hybrids and these compounds were evaluated against different tumor cell lines. This structural pattern was designed considering the cytotoxic potential already known for eugenol, chalcones and isoxazoles. Notably, chalcones 7, 9, 10, and 11 displayed significant activity (4.2-14.5 µM) against two cancer cell lines, surpassing the potency of the control drug doxorubicin. The reaction of chalcones with hydroxylamine hydrochloride provided the corresponding isoxazoles that were inactive against these cancer cells. The dihydroeugenol chalcone 7 showed the most promising results, demonstrating higher potency against HepG2 (CC50: 4.2 µM) and TOV-21G (CC50: 7.2 µM). Chalcone 7 was also three times less toxic than doxorubicin considering HepG2 cells, with a selectivity index greater than 11. Further investigations including clonogenic survival, cell cycle progression and cell migration assays confirmed the compelling antitumoral potential of chalcone 7, as it reduced long-term survival due to DNA fragmentation, inducing cell death and inhibiting HepG2 cells migration. Moreover, in silico studies involving docking and molecular dynamics revealed a consistent binding mode of chalcone 7 with metalloproteinases, particularly MMP-9, shedding light on its potential mechanism of action related to anti-migratory effects. These significant findings suggest the inclusion of compound 7 as a promising candidate for future studies in the field of cancer therapeutics.
Subject(s)
Antineoplastic Agents , Chalcone , Chalcones , Neoplasms , Chalcone/pharmacology , Chalcone/chemistry , Chalcones/pharmacology , Chalcones/chemistry , Eugenol/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Doxorubicin/pharmacology , Isoxazoles/pharmacology , Cell Proliferation , Molecular Structure , Drug Screening Assays, Antitumor , Molecular Docking Simulation , Structure-Activity RelationshipABSTRACT
Neglected tropical diseases (NTDs) are prevalent in tropical and subtropical countries, and schistosomiasis is among the most relevant diseases worldwide. In addition, one of the two biggest problems in developing drugs against this disease is related to drug resistance, which promotes the demand to develop new drug candidates for this purpose. Thus, one of the drug targets most explored, Schistosoma mansoni Cathepsin B1 (SmCB1 or Sm31), provides new opportunities in drug development due to its essential functions for the parasite's survival. In this way, here, the latest developments in drug design studies targeting SmCB1 were approached, focusing on the most promising analogs of nitrile, vinyl sulphones, and peptidomimetics. Thus, it was shown that despite being a disease known since ancient times, it remains prevalent throughout the world, with high mortality rates. The therapeutic arsenal of antischistosomal drugs consists only of praziquantel, which is widely used for this purpose and has several advantages, such as efficacy and safety. However, it has limitations, such as the impossibility of acting on the immature worm and exploring new targets to overcome these limitations. SmCB1 shows its potential as a cysteine protease with a catalytic triad consisting of Cys100, His270, and Asn290. Thus, design studies of new inhibitors focus on their catalytic mechanism for designing new analogs. In fact, nitrile and sulfonamide analogs show the most significant potential in drug development, showing that these chemical groups can be better exploited in drug discovery against schistosomiasis. We hope this manuscript guides the authors in searching for promising new antischistosomal drugs.
ABSTRACT
A large family of enzymes with the function of hydrolyzing peptide bonds, called peptidases or cysteine proteases (CPs), are divided into three categories according to the peptide chain involved. CPs catalyze the hydrolysis of amide, ester, thiol ester, and thioester peptide bonds. They can be divided into several groups, such as papain-like (CA), viral chymotrypsin-like CPs (CB), papain-like endopeptidases of RNA viruses (CC), legumain-type caspases (CD), and showing active residues of His, Glu/Asp, Gln, Cys (CE). The catalytic mechanism of CPs is the essential cysteine residue present in the active site. These mechanisms are often studied through computational methods that provide new information about the catalytic mechanism and identify inhibitors. The role of computational methods during drug design and development stages is increasing. Methods in Computer-Aided Drug Design (CADD) accelerate the discovery process, increase the chances of selecting more promising molecules for experimental studies, and can identify critical mechanisms involved in the pathophysiology and molecular pathways of action. Molecular dynamics (MD) simulations are essential in any drug discovery program due to their high capacity for simulating a physiological environment capable of unveiling significant inhibition mechanisms of new compounds against target proteins, especially CPs. Here, a brief approach will be shown on MD simulations and how the studies were applied to identify inhibitors or critical information against cysteine protease from several microorganisms, such as Trypanosoma cruzi (cruzain), Trypanosoma brucei (rhodesain), Plasmodium spp. (falcipain), and SARS-CoV-2 (Mpro). We hope the readers will gain new insights and use our study as a guide for potential compound identifications using MD simulations.