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Acute myeloid leukemia (AML) is one of the cancers that grow most aggressively. The challenges in AML management are huge, despite many treatment options. Mutations in FLT3 tyrosine kinase receptors make the currently available therapies less responsive. Therefore, there is a need to find new lead molecules that can specifically target mutated FLT3 to block growth factor signaling and inhibit AML cell proliferation. Our previous studies on FLT3-mutated AML cells demonstrated that ß-elemene and compound 5a showed strong inhibition of proliferation by blocking the mutated FLT3 receptor and altering the key apoptotic genes responsible for apoptosis. Furthermore, we hypothesized that both ß-elemene and compound 5a could be therapeutically effective. Therefore, combining these drugs against mutated FLT3 cells could be promising. In this context, dose-matrix combination-based cellular inhibition analyses, cell morphology studies and profiling of 43 different apoptotic protein targets via combinatorial treatment were performed. Our studies provide strong evidence for the hypothesis that ß-elemene and compound 5a combination considerably increased the therapeutic potential of both compounds by enhancing the activation of several key targets implicated in AML cell death.
Assuntos
Leucemia Mieloide Aguda , Humanos , Oxindóis/farmacologia , Linhagem Celular Tumoral , Leucemia Mieloide Aguda/metabolismo , Mutação , Apoptose , Tirosina Quinase 3 Semelhante a fms/genética , Inibidores de Proteínas Quinases/farmacologiaRESUMO
ATP-binding cassette transporter G2 (ABCG2) is an efflux transporter related to the clinical multidrug resistance (MDR) phenomenon. Identifying ABCG2 inhibitors could help discover extraordinary curative strategies for carcinoma remediation. Hitherto, there is no medication drug inhibiting ABCG2 transporter, notwithstanding that a considerable number of drugs have been submitted to clinical-trial and investigational phases. In the search for unprecedented chemical compounds that could inhibit the ABCG2 transporter, an in silico screening was conducted on the Naturally Occurring Plant-based Anticancer Compound-Activity-Target (NPACT) database containing 1574 compounds. Inhibitor-ABCG2 binding affinities were estimated based on molecular docking and molecular minimization (MM) calculations and compared to a co-crystallized inhibitor (BWQ) acting as a reference inhibitor. Molecular dynamics (MD) simulations pursued by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations were further executed for compounds with MM-GBSA//MM binding energies lower than BWQ (calc. - 60.5 kcal/mol). NPACT00968 and NPACT01545 demonstrated auspicious inhibitory activities according to binding affinities (ΔGbinding) over the 100 ns MD simulations that were nearly one and a half folds compared to BWQ (- 100.4, - 94.7, and - 62.9 kcal/mol, respectively). Throughout the 100 ns MD simulations, structural and energetical analyses unveiled outstanding stability of the ABCG2 transporter when bound with NPACT00968 and NPACT01545. In silico calculations hold a promise for those two inhibitors as drug candidates of ABCG2 transporter and emphasize that further in vitro and in vivo experiments are guaranteed.
Assuntos
Antineoplásicos , Resistencia a Medicamentos Antineoplásicos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Simulação de Acoplamento Molecular , Estudos Prospectivos , Antineoplásicos/química , Descoberta de DrogasRESUMO
Sulphonamide and 1,3,4-oxadiazole moieties are present as integral structural parts of many drugs and pharmaceuticals. Taking into account the significance of these moieties, we herein present the synthesis, single-crystal X-ray analysis, DFT studies, and α-amylase inhibition of probenecid derived two S-alkylphthalimide-oxadiazole-benzenesulfonamide hybrids. The synthesis has been accomplished in high yields. The final structures of both hybrids have been established completely with the help of different spectro-analytical techniques, including NMR, FTIR, HR-MS, and single-crystal X-ray diffraction analyses. In an effort to confirm the experimental findings, versatile quantum mechanical calculations and Hirshfeld Surface analysis have been performed. α-Amylase inhibition assay has been executed to investigate the enzyme inhibitory potential of both hybrids. The low IC50 value (76.92 ± 0.19 µg/mL) of hybrid 2 shows the good α-amylase inhibition potential of the respective compound. Ultimately, the binding affinities and features of the two hybrids are elucidated utilising a molecular docking technique against the α-amylase enzyme.
Assuntos
Oxidiazóis , alfa-Amilases , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxidiazóis/farmacologia , Probenecid , Sulfonamidas/química , Sulfonamidas/farmacologia , Difração de Raios X , BenzenossulfonamidasRESUMO
In the current study, unexplored type IV halogenâ¯halogen interaction was thoroughly elucidated, for the first time, and compared to the well-established types I−III interactions by means of the second-order Møller−Plesset (MP2) method. For this aim, the halobenzeneâ¯halobenzene homodimers (where halogen = Cl, Br, and I) were designed into four different types, parodying the considered interactions. From the energetic perspective, the preference of scouted homodimers was ascribed to type II interactions (i.e., highest binding energy), whereas the lowest binding energies were discerned in type III interactions. Generally, binding energies of the studied interactions were observed to decline with the decrease in the σ-hole size in the order, C6H5Iâ¯IC6H5 > C6H5Brâ¯BrC6H5 > C6H5Clâ¯ClC6H5 homodimers and the reverse was noticed in the case of type IV interactions. Such peculiar observations were relevant to the ample contributions of negative-beltâ¯negative-belt interactions within the C6H5Clâ¯ClC6H5 homodimer. Further, type IV torsional trans â cis interconversion of C6H5Xâ¯XC6H5 homodimers was investigated to quantify the πâ¯π contributions into the total binding energies. Evidently, the energetic features illustrated the amelioration of the considered homodimers (i.e., more negative binding energy) along the prolonged scope of torsional trans â cis interconversion. In turn, these findings outlined the efficiency of the cis configuration over the trans analog. Generally, symmetry-adapted perturbation theory-based energy decomposition analysis (SAPT-EDA) demonstrated the predominance of all the scouted homodimers by the dispersion forces. The obtained results would be beneficial for the omnipresent studies relevant to the applications of halogen bonds in the fields of materials science and crystal engineering.
Assuntos
Halogênios , Hidrocarbonetos Halogenados , Benzeno , Halogênios/química , Modelos TeóricosRESUMO
The effects of Lewis basicity and acidity on σ-hole interactions were investigated using two sets of carbon-containing complexes. In Set I, the effect of Lewis basicity was studied by substituting the X3/X atom(s) of the NC-C6H2-X3 and NCX Lewis bases (LB) with F, Cl, Br, or I. In Set II, the W-C-F3 and F-C-X3 (where X and W = F, Cl, Br, and I) molecules were utilized as Lewis acid (LA) centers. Concerning the Lewis basicity effect, higher negative interaction energies (Eint) were observed for the F-C-F3âââNC-C6H2-X3 complexes compared with the F-C-F3âââNCX analogs. Moreover, significant Eint was recorded for Set I complexes, along with decreasing the electron-withdrawing power of the X3/X atom(s). Among Set I complexes, the highest negative Eint was ascribed to the F-C-F3âââNC-C6H2-I3 complex with a value of -1.23 kcal/mol. For Set II complexes, Eint values of F-C-X3 bearing complexes were noted within the -1.05 to -2.08 kcal/mol scope, while they ranged from -0.82 to -1.20 kcal/mol for the W-C-F3 analogs. However, Vs,max quantities exhibited higher values in the case of W-C-F3 molecules compared with F-C-X3; preferable negative Eint were ascribed to the F-C-X3 bearing complexes. These findings were delineated as a consequence of the promoted contributions of the X3 substituents. Dispersion forces (Edisp) were identified as the dominant forces for these interactions. The obtained results provide a foundation for fields such as crystal engineering and supramolecular chemistry studies that focus on understanding the characteristics of carbon-bearing complexes.
Assuntos
Carbono , Bases de Lewis , Bases de Lewis/química , Ácidos de Lewis/química , ElétronsRESUMO
BACKGROUND: The current study utilizes in silico molecular docking/molecular dynamics to evaluate the binding affinity of apigenin and safranal with 5HT1AR/5HT2AR, followed by assessment of in vivo effects of these compounds on depressive and anxious behavior. METHODS: The docking between apigenin and safranal and the 5HT1A and 5HT2A receptors was performed utilizing AutoDock Vina software, while MD and protein-lipid molecular dynamics simulations were executed by AMBER16 software. For in vivo analysis, healthy control (HC), disease control (DC), fluoxetine-, and apigenin-safranal-treated rats were tested for changes in depression and anxiety using the forced swim test (FST) and the elevated plus-maze test (EPMT), respectively. RESULTS: The binding affinity estimations identified the superior interacting capacity of apigenin over safranal for 5HT1A/5HT2A receptors over 200 ns MD simulations. Both compounds exhibit oral bioavailability and absorbance. In the rodent model, there was a significant increase in the overall mobility time in the FST, while in the EPMT, there was a decrease in latency and an increase in the number of entries for the treated and HC rats compared with the DC rats, suggesting a reduction in depressive/anxiety symptoms after treatment. CONCLUSIONS: Our analyses suggest apigenin and safranal as prospective medication options to treat depression and anxiety.
Assuntos
Apigenina , Simulação de Dinâmica Molecular , Ratos , Animais , Simulação de Acoplamento Molecular , Apigenina/farmacologia , Depressão/tratamento farmacológico , Estudos Prospectivos , Ansiedade/tratamento farmacológico , LipídeosRESUMO
Novel pyrrolo [2,3-b] pyrrole derivatives were synthesized and their hypolipidemic activity was assessed in hyperlipidemic rats. The chemical structures of the new derivatives were confirmed through spectral analysis. Compounds 5 and 6 were revealed to be the most effective hypolipidemic agents, with considerable hypocholesterolemic and hypotriglyceridemic effects. They appear to be promising candidates for creating new powerful derivatives with anti-atherosclerotic and hypolipidemic properties. As for antimicrobial activity, some of the tested compounds showed moderate activity against Pseudomonas aeruginosa: compound 2 revealed an MIC value of 50 µg/mL, compared to 25 µg/mL for ciprofloxacin. Compound 3 showed good antimicrobial activity against Staphylococcus aureus, comparable to ciprofloxacin, and roughly half the activity of ampicillin, according to MIC values. Compound 2 has an MIC approximately 25% of that of clotrimazole against Candida albicans. Compound 2 also showed the highest antioxidant activity with 59% inhibition of radical scavenging activity. Additionally, the cytotoxic activity of these new derivatives 1-7 was investigated and most of them showed good anticancer activity against the three tested cell lines.
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Anti-Infecciosos , Pirróis , Animais , Antibacterianos/química , Anti-Infecciosos/farmacologia , Ciprofloxacina , Testes de Sensibilidade Microbiana , Micro-Ondas , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirróis/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
The P-glycoprotein (P-gp/ABCB1) is responsible for a xenobiotic efflux pump that shackles intracellular drug accumulation. Additionally, it is included in the dud of considerable antiviral and anticancer chemotherapies because of the multidrug resistance (MDR) phenomenon. In the search for prospective anticancer drugs that inhibit the ABCB1 transporter, the Natural Product Activity and Species Source (NPASS) database, containing >35,000 molecules, was explored for identifying ABCB1 inhibitors. The performance of AutoDock4.2.6 software to anticipate ABCB1 docking score and pose was first assessed according to available experimental data. The docking scores of the NPASS molecules were predicted against the ABCB1 transporter. Molecular dynamics (MD) simulations were conducted for molecules with docking scores lower than taxol, a reference inhibitor, pursued by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations. On the basis of MM-GBSA calculations, five compounds revealed promising binding affinities as ABCB1 inhibitors with ΔGbinding < −105.0 kcal/mol. The binding affinity and stability of the identified inhibitors were compared to the chemotherapeutic agent. Structural and energetical analyses unveiled great steadiness of the investigated inhibitors within the ABCB1 active site throughout 100 ns MD simulations. Conclusively, these findings point out that NPC104372, NPC475164, NPC2313, NPC197736, and NPC477344 hold guarantees as potential ABCB1 drug candidates and warrant further in vitro/in vivo tests.
Assuntos
Antineoplásicos , Produtos Biológicos , Antineoplásicos/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Produtos Biológicos/farmacologia , Descoberta de Drogas , Estudos ProspectivosRESUMO
For the first time, σ-hole interactions within likeâ¯like carbon-containing complexes were investigated, in both the absence and presence of the external electric field (EEF). The effects of the directionality and strength of the utilized EEF were thoroughly unveiled in the (F-C-F3)2, (F-C-H3)2, and (H-C-F3)2 complexes. In the absence of the EEF, favorable interaction energies, with negative values, are denoted for the (F-C-F3)2 and (H-C-F3)2 complexes, whereas the (F-C-H3)2 complex exhibits unfavorable interactions. Remarkably, the strength of the applied EEF exhibits a prominent role in turning the repulsive forces within the latter complex into attractive ones. The symmetrical nature of the considered likeâ¯like carbon-containing complexes eradicated the effect of directionality of the EEF. The quantum theory of atoms in molecules (QTAIM), and the noncovalent interaction (NCI) index, ensured the occurrence of the attractive forces, and also outlined the substantial contributions of the three coplanar atoms to the total strength of the studied complexes. Symmetry-adapted perturbation theory (SAPT) results show the dispersion-driven nature of the interactions.
Assuntos
Carbono , Teoria Quântica , Eletricidade , Eletricidade EstáticaRESUMO
In the present study, two new series of pyrrolizines bearing 3,4,5-trimethoxyphenyl moiety were designed, synthesised, and evaluated for their cytotoxic activity. The benzamide derivatives 16a-e showed higher cytotoxicity than their corresponding Schiff bases 15a-e. Compounds 16a,b,d also inhibited the growth of MCF-7/ADR cells with IC50 in the range of 0.52-6.26 µM. Interestingly, the new compounds were less cytotoxic against normal MRC-5 cells (IC50=0.155-17.08 µM). Mechanistic studies revealed the ability of compounds 16a,b,d to inhibit tubulin polymerisation and multiple oncogenic kinases. Moreover, compounds 16a,b,d induced preG1 and G2/M cell cycle arrest and early apoptosis in MCF-7 cells. The molecular docking analyses of compounds 16a,b,d into the active site in tubulin, CDK-2, and EGFR proteins revealed higher binding affinities compared to the co-crystallised ligands. These preliminary results suggested that compounds 16a,b,d could serve as promising lead compounds for the future development of new potent anticancer agents.HighlightsTwo new series of pyrrolizines bearing 3,4,5-trimethoxyphenyl moieties were synthesized.Compounds 16a,b,d displayed the highest cytotoxicity against the three cancer cell lines.Kinase profiling test revealed inhibition of multiple oncogenic kinases by compounds 16a,b,d.Compounds 16a,b,d exhibited weak to moderate inhibition of tubulin-polymerization.Compounds 16a,b,d induced preG1 and G2/M cell cycle arrest and early apoptosis in MCF-7 cells.Docking studies revealed high binding affinities for compounds 16a,b towards tubulin and CDK-2.
Assuntos
Antineoplásicos/farmacologia , Simulação de Acoplamento Molecular/métodos , Pirazóis/química , Antineoplásicos/química , Desenho de Fármacos , Humanos , Células MCF-7 , Tubulina (Proteína)/químicaRESUMO
In the current study, virtual screening of a small library of 1302 pyrrolizines bearing urea/thiourea moieties was performed. The top-scoring hits were synthesised and evaluated for their cytotoxicity against three cancer (MCF-7, A2780, and HT29) and one normal (MRC-5) cell lines. The results of the MTT assay revealed potent cytotoxic activities for most of the new compounds (IC50 = 0.16-34.13 µM). The drug-likeness study revealed that all the new compounds conform to Lipinski's rule. Mechanistic studies of compounds 18 b, 19a, and 20a revealed the induction of apoptosis and cell cycle arrest at the G1 phase in MCF-7 cells. The three compounds also displayed potent inhibitory activity against CDK-2 (IC50 = 25.53-115.30 nM). Moreover, the docking study revealed a nice fitting of compound 19a into the active sites of CDK-2/6/9. These preliminary results suggested that compound 19a could serve as a promising scaffold in the discovery of new potent anticancer agents.
Assuntos
Antineoplásicos/farmacologia , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Pirróis/farmacologia , Ureia/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 2 Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/químicaRESUMO
We report herein a new series of synthesized N-substituted-2-quinolonylacetohydrazides aiming to evaluate their activity towards SARS-CoV-2. The structures of the obtained products were fully confirmed by NMR, mass, IR spectra and elemental analysis as well. Molecular docking calculations showed that most of the tested compounds possessed good binding affinity to the SARS-CoV-2 main protease (Mpro) comparable toRemdesivir.
RESUMO
In the current study, a 2D similarity/docking-based study was used to predict the potential binding modes of icotinib, almonertinib, and olmutinib into EGFR. The similarity search of icotinib, almonertinib, and olmutinib against a database of 154 EGFR ligands revealed the highest similarity scores with erlotinib (0.9333), osimertinib (0.9487), and WZ4003 (0.8421), respectively. In addition, the results of the docking study of the three drugs into EGFR revealed high binding free energies (ΔGb = -6.32 to -8.42 kcal/mol) compared to the co-crystallized ligands (ΔGb = -7.03 to -8.07 kcal/mol). Analysis of the top-scoring poses of the three drugs was done to identify their potential binding modes. The distances between Cys797 in EGFR and the Michael acceptor sites in almonertinib and olmutinib were determined. In conclusion, the results could provide insights into the potential binding characteristics of the three drugs into EGFR which could help in the design of new more potent analogs.
Assuntos
Acrilamidas/farmacologia , Éteres de Coroa/farmacologia , Indóis/farmacologia , Simulação de Acoplamento Molecular , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Quinazolinas/farmacologia , Acrilamidas/química , Sítios de Ligação/efeitos dos fármacos , Éteres de Coroa/química , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Indóis/química , Ligantes , Estrutura Molecular , Piperazinas/química , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Quinazolinas/químicaRESUMO
In the current study, a simple in silico approach using free software was used with the experimental studies to optimize the antiproliferative activity and predict the potential mechanism of action of pyrrolizine-based Schiff bases. A compound library of 288 Schiff bases was designed based on compound 10, and a pharmacophore search was performed. Structural analysis of the top scoring hits and a docking study were used to select the best derivatives for the synthesis. Chemical synthesis and structural elucidation of compounds 16a-h were discussed. The antiproliferative activity of 16a-h was evaluated against three cancer (MCF7, A2780 and HT29, IC50 = 0.01-40.50 µM) and one normal MRC5 (IC50 = 1.27-24.06 µM) cell lines using the MTT assay. The results revealed the highest antiproliferative activity against MCF7 cells for 16g (IC50 = 0.01 µM) with an exceptionally high selectivity index of (SI = 578). Cell cycle analysis of MCF7 cells treated with compound 16g revealed a cell cycle arrest at the G2/M phase. In addition, compound 16g induced a dose-dependent increase in apoptotic events in MCF7 cells compared to the control. In silico target prediction of compound 16g showed six potential targets that could mediate these activities. Molecular docking analysis of compound 16g revealed high binding affinities toward COX-2, MAP P38α, EGFR, and CDK2. The results of the MD simulation revealed low RMSD values and high negative binding free energies for the two complexes formed between compound 16g with EGFR, and CDK2, while COX-2 was in the third order. These results highlighted a great potentiality for 16g to inhibit both CDK2 and EGFR. Taken together, the results mentioned above highlighted compound 16g as a potential anticancer agent.
Assuntos
Antineoplásicos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Modelos Biológicos , Simulação de Acoplamento Molecular , Pirróis , Software , Antineoplásicos/química , Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HT29 , Humanos , Células MCF-7 , Pirróis/química , Pirróis/farmacologia , Bases de Schiff/química , Bases de Schiff/farmacologiaRESUMO
A mild and versatile method based on Cu-catalyzed [2+3] cycloaddition (Huisgen-Meldal-Sharpless reaction) was developed to tether 3,3'-((4-(prop-2-yn-1-yloxy)phenyl)methylene)bis(4-hydroxyquinolin-2(1H)-ones) with 4-azido-2-quinolones in good yields. This methodology allowed attaching three quinolone molecules via a triazole linker with the proposed mechanism. The products are interesting precursors for their anti-proliferative activity. Compound 8g was the most active one, achieving IC50 = 1.2 ± 0.2 µM and 1.4 ± 0.2 µM against MCF-7 and Panc-1 cell lines, respectively. Moreover, cell cycle analysis of cells MCF-7 treated with 8g showed cell cycle arrest at the G2/M phase (supported by Caspase-3,8,9, Cytochrome C, BAX, and Bcl-2 studies). Additionally, significant pro-apoptotic activity is indicated by annexin V-FITC staining.
Assuntos
Química Click/métodos , Quinolonas/química , Triazóis/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cobre/química , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Humanos , Células MCF-7 , Estrutura Molecular , Quinolonas/síntese química , Relação Estrutura-Atividade , Triazóis/síntese químicaRESUMO
Improving the light-harvesting efficiency and boosting open circuit voltage are crucial challenges for enhancing the efficiency of organic solar cells. This work introduces seven new molecules (SA1-SA7) to upgrade the optoelectronic and photovoltaic properties of Q-C-F molecule-based solar cells. All recently designed molecules have the same alkyl-substituted Quinoxaline core and CPDT donor but vary in the end-capped acceptor subunits. All the investigated molecules have revealed superior properties than the model (R) by having absorbance ranging from 681 nm to 782 nm in the gaseous medium while 726 nm-861 nm in chloroform solvent, with the lowest band gap ranging from 1.91 to 2.19 eV SA1 molecule demonstrated the highest λmax (861 nm) in chloroform solvent and the lowest band gap (1.91 eV). SA2 molecule has manifested highest dipole moment (4.5089 D), lower exciton binding energy in gaseous (0.33 eV) and chloroform solvent (0.47 eV), and lower charge mobility of hole (0.0077693) and electron (0.0042470). At the same time, SA7 showed the highest open circuit voltage (1.56 eV) and fill factor (0.9166) due to solid electron-pulling acceptor moieties. From these supportive outcomes, it is inferred that our computationally investigated molecules may be promising candidates to be used in advanced versions of OSCs in the upcoming period.
Assuntos
Clorofórmio , Quinoxalinas , Elétrons , Gases , SolventesRESUMO
Developing proficient organic solar cells with improved optoelectronic properties is still a matter of concern. In the current study, with an aspiration to boost the optoelectronic properties and proficiency of organic solar cells, seven new small-molecule acceptors (Db1-Db7) are presented by altering the central core of the reference molecule (DBD-4F). The optoelectronic aspects of DBD-4F and Db1-Db7 molecules were explored using the density functional theory (DFT) approach, and solvent-state calculations were assessed utilizing TD-SCF simulations. It was noted that improvement in photovoltaic features was achieved by designing these molecules. The results revealed a bathochromic shift in absorption maxima (λmax) of designed molecules reaching up to 776 nm compared to 736 nm of DBD-4F. Similarly, a narrow band gap, low excitation energy, and reduced binding energy were also observed in newly developed molecules in comparison with the pre-existing DBD-4F molecule. Performance improvement can be indicated by the high light-harvesting efficiency (LHE) of designed molecules (ranging from 0.9992 to 0.9996 eV) compared to the reference having a 0.9991 eV LHE. Db4 and Db5 exhibited surprisingly improved open-circuit voltage (V OC) values up to 1.64 and 1.67 eV and a fill factor of 0.9198 and 0.9210, respectively. Consequently, these newly designed molecules can be considered in the future for practical use in manufacturing OSCs with improved optoelectronic and photovoltaic attributes.
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Since 2020, many compounds have been investigated for their potential use in the treatment of SARS-CoV-2 infection. Among these agents, a huge number of natural products and FDA-approved drugs have been evaluated as potential therapeutics for SARS-CoV-2 using virtual screening and docking studies. However, the identification of the molecular targets involved in viral replication led to the development of rationally designed anti-SARS-CoV-2 agents. Among these targets, the main protease (Mpro) is one of the key enzymes needed in the replication of the virus. The data gleaned from the crystal structures of SARS-CoV-2 Mpro complexes with small-molecule covalent inhibitors has been used in the design and discovery of many highly potent and broad-spectrum Mpro inhibitors. The current review focuses mainly on the covalent type of SARS-CoV-2 Mpro inhibitors. The design, chemistry, and classification of these inhibitors were also in focus. The biological activity of these inhibitors, including their inhibitory activities against Mpro, their antiviral activities, and the SAR studies, were discussed. The review also describes the potential mechanism of the interaction between these inhibitors and the catalytic Cys145 residue in Mpro. Moreover, the binding modes and key binding interactions of these covalent inhibitors were also illustrated. The covalent inhibitors discussed in this review were of diverse chemical nature and origin. Their antiviral activity was mediated mainly by the inhibition of SARS-CoV-2 Mpro, with IC50 values in the micromolar to the nanomolar range. Many of these inhibitors exhibited broad-spectrum inhibitory activity against the Mpro enzymes of other coronaviruses (SARS-CoV-1 and MERS-CoV). The dual inhibition of the Mpro and PLpro enzymes of SARS-CoV-2 could also provide higher therapeutic benefits than Mpro inhibition. Despite the approval of nirmatrelvir by the FDA, many mutations in the Mpro enzyme of SARS-CoV-2 have been reported. Although some of these mutations did not affect the potency of nirmatrelvir, there is an urgent need to develop a second generation of Mpro inhibitors. We hope that the data summarized in this review could help researchers in the design of a new potent generation of SARS-CoV-2 Mpro inhibitors.
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This study focused on modeling and density functional theory (DFT) analysis of reference (AI1) and designed structures (AI11-AI15), based on the thieno-imidazole core, in order to create profitable candidates for solar cells. All the optoelectronic properties of the molecular geometries were computed using DFT and time dependent-DFT approaches. The influence of terminal acceptors on the bandgaps, absorption, hole and electron mobilities, charge transfer capabilities, fill factor, dipole moment, etc. Of the recently designed structures (AI11-AI15), as well as reference (AI1), were evaluated. Optoelectronics and chemical parameters of newly architecture geometries were shown to be superior to the cited molecule. The FMOs and DOS graphs also demonstrated that the linked acceptors remarkably improved the dispersion of charge density in the geometries under study, particularly in AI11 and AI14. Calculated values of binding energy and chemical potential confirmed the thermal stability of the molecules. All the derived geometries surpassed the AI1 (Reference) molecule in terms of maximum absorbance ranging from 492 to 532 nm (in chlorobenzene solvent) and a narrower bandgap ranging from 1.76 to 1.99eV. AI15 had the lowest exciton dissociation energy of 0.22eV as well as lowest electrons and hole dissociation energies, while AI11 and AI14 showed highest VOC, fill factor, power conversion efficiency (PCE), IP and EA (owing to presence of strong electron pulling cyano (CN) moieties at their acceptor portions and extended conjugation) than all the examined molecules, implying that they could be used to build elite solar cells with enhanced photovoltaic attributes.
Assuntos
Elétrons , Cloreto de Sódio , Teoria da Densidade Funcional , SolventesRESUMO
In the current DFT study, seven dimethoxyl-indaceno dithiophene based semiconducting acceptor molecules (ID1-ID7) are designed computationally by modifying the parent molecule (IDR). Here, based on a DFT exploration at a carefully selected level of theory, we have compiled a list of the optoelectronic properties of ID1-ID7 and IDR. In light of these results, all newly designed molecules, except ID5 have shown a bathochromic shift in their highest absorbance (λ max). ID1-ID4, ID6 and ID7 molecules have smaller band gap (E gap) and excitation energy (E x). IP of ID5 is the smallest and EA of ID1 is the largest among all others. Compared to the parent molecule, ID1-ID3 have increased electron mobility, with ID1 being the most improved in hole mobility. ID4 had the best light harvesting efficiency in this investigation, due to its strongest oscillator. The acceptor molecules' open-circuit voltages (V OC) were computed after being linked to the PTB7-Th donor molecule. Fill factor (FF) and normalized V OC of ID1-ID7 were calculated and compared to the parent molecule. Based on the outcomes of this study, the modified acceptors may be further scrutinised for empirical usage in the production of organic solar cells with enhanced photovoltaic capabilities.