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The synthesis of fatty acids, which are essential for the growth and survival of bacterial cells, is catalyzed by beta-keto acyl-ACP synthase I-III. Due to the significant differences between the bacterial ACP synthase enzyme and the mammalian enzyme, it may serve as a viable target for the development of potent anti-bacterial medications. In this study, a sophisticated molecular docking strategy was employed to target all three KAS enzymes. Initially, 1000 fluoroquinolone derivatives were obtained from PubChem database, along with the commonly used ciprofloxacin, and subjected to virtual screening against FabH, FabB, and FabF, respectively. Subsequently, molecular dynamics (MD) simulations were conducted to confirm the stability and reliability of the generated conformations. The compounds 155813629, 142486676, and 155567217 were found to exhibit potential molecular interactions against FabH, FabB, and FabF, respectively, with docking scores of -9.9, -8.9, and -9.9 kcal/mol. These scores outperformed the docking score of standard ciprofloxacin. Furthermore, MD simulations were used to assess the dynamic nature of molecular interactions in both physiological and dynamic settings. Throughout the simulated trajectory, all three complexes displayed favorable stability patterns. The findings of this investigation suggest that fluoroquinolone derivatives may serve as highly effective and selective inhibitors of the KAS enzyme.
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3-Oxoacil-(Proteína de Transporte de Acila) Sintase , Fluoroquinolonas , Simulação de Acoplamento Molecular , Fluoroquinolonas/farmacologia , Reprodutibilidade dos Testes , Antibacterianos/farmacologia , Ciprofloxacina/farmacologia , Inibidores Enzimáticos/farmacologiaRESUMO
Currently, drug resistance to commercially available antibiotics is imparting negative consequences to global health, and the development of novel antibiotics in a timely manner is a prime need of the hour. In the current study, an e-pharmacophore model was built using the 3D structure of DNA gyrase in complex with a standard inhibitor. The generated model was subjected to a pharmacophore based virtual screening against 45,257,086 molecules having 223,460,579 conformers available in MCULE database. Pharmacophore based screening retrieved eight molecules as top hit based on pharmacophoric features in comparison to standard inhibitors. Afterward, all eight compounds were subjected molecular docking based on deep learning algorithm. The molecular docking revealed that compound MCULE-6042843173 and MCULE-2362244223 had significant binding orientation inside active pocket of targeted protein with binding affinity of -9.52 and -9.24 kcal/mol respectively. In addition, density functional theory studies (DFT) were performed to evaluate quantum mechanics of top ranked compounds which were investigated through quantum mechanics (QM) computations which strongly assisted the findings of other in-silico investigations. Consequently, the MCULE-6042843173 and MCULE-2362244223 were subjected to MD simulation studies for evaluation of stability, hydrogen bond analysis, van der Waals interactions, and the contact profile of compounds with targeted amino acid residues. Findings of current study suggested MCULE-6042843173 and MCULE-2362244223 as potential and novel inhibitor of DNA Gyrase enzyme.
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The study aimed to improve the treatment of impetigo with naturally occurring quercetin and its copper-quercetin (Cu-Q) complex by preparing sustained-release (SR) nanoparticles of polycaprolactone (PCL). The solvent evaporation method was used for the copper-quercetin (Cu-Q) complex formation, and their PCL nanoparticles (PCL-NPs, Q-PCL-NPs, and Cu-Q-PCL-NPs) were prepared by the high-pressure homogenization method. Synthesis of nanoparticles was confirmed by their physicochemical and antibacterial properties of quercetin against Gram-positive as well as Gram-negative bacteria. The percentage loading efficiency of quercetin and release in 100 mM of phosphate buffer pH 7.4 and 5.5 at 37 °C was found to be more than 90% after 24 h with the zero-order release pattern. Minimum inhibitory concentration of nanoparticles was found to increase threefold in the case of Cu-Q-PCL-NPs may be due to the synergistic antibacterial behavior. Scanning electron microscopy showed spherical nanoparticles, and surface roughness was confirmed by atomic force microscopy analysis. Fortunately, no sign of irritation on rat skin even at 3%, was seen. In vitro antioxidant assay by 2,2-diphenyl-1-picrylhydrazyl reduction was found to be ≤80 ± 0.02% which confirmed their scavenging activity. Interestingly, for the ex vivo study, the tape-stripping model was applied against Staphylococcus aureus containing rats and showed the formation of the epidermal layer within 4-5 days. Confirmation of antibacterial activity of pure quercetin, from Cu-Q complex, and their SR release from Q-PCL-NPs and Cu-Q-PCL-NPs was considered an effective tool for the treatment of skin diseases and can be used as an alternative of already resistant ciprofloxacin in impetigo.
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Impetigo , Nanopartículas , Ratos , Animais , Quercetina/farmacologia , Quercetina/uso terapêutico , Quercetina/química , Cobre/química , Preparações de Ação Retardada , Nanopartículas/química , Antibacterianos/farmacologia , Antibacterianos/químicaRESUMO
Deposition of hydroxyapatite (HA) or alkaline phosphate crystals on soft tissues causes the pathological calcification diseases comprising of end-stage osteoarthritis (OA), ankylosing spondylitis (AS), medial artery calcification and tumour calcification. The pathological calcification is symbolised by increased concentration of tissue non-specific alkaline phosphatase (TNAP). An efficient therapeutic strategy to eradicate these diseases is required, and for this the alkaline phosphatase inhibitors can play a potential role. In this context a series of novel quinolinyl iminothiazolines was synthesised and evaluated for alkaline phosphatase inhibition potential. All the compounds were subjected to DFT studies where N-benzamide quinolinyl iminothiazoline (6g), N-dichlorobenzamide quinolinyl iminothiazoline (6i) and N-nitrobenzamide quinolinyl iminothiazoline (6j) were found as the most reactive compounds. Then during the in-vitro testing, the compound N-benzamide quinolinyl iminothiazoline (6g) exhibited the maximum alkaline phosphatase inhibitory effect (IC50 = 0.337 ± 0.015 µM) as compared to other analogues and standard KH2PO4 (IC50 = 5.245 ± 0.477 µM). The results were supported by the molecular docking studies, molecular dynamics simulations and kinetic analysis which also revealed the inhibitory potential of compound N-benzamide quinolinyl iminothiazoline (6g) against alkaline phosphatase. This compound can be act as lead molecule for the synthesis of more effective inhibitors and can be suggested to test at the molecular level.
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Fosfatase Alcalina , Inibidores Enzimáticos , Simulação de Acoplamento Molecular , Cinética , Fosfatase Alcalina/metabolismo , Inibidores Enzimáticos/química , Benzamidas/farmacologiaRESUMO
The Epidermal Growth Factor Receptor (EGFR) is an important therapeutic target for the treatment of a variety of epithelial malignancies, including breast cancer, in which EGFR is aberrantly expressed.The fluorocyclopentenyl-purine-pyrimidines derivatives, which have previously been described as powerful compounds against breast cancer, were selected to investigate their potential against EGFR using computational tools in an effort to obtain potent inhibitors with fewer adverse effects. The molecule's chemical reactivity and stability were assessed by determining the HOMO-LUMO energy gap using density functional theory (DFT) calculations. Among all the selected compounds, PU4 displayed a HOMO-LUMO gap of 0.191â eV. Additionally, molecular docking analysis was performed to assess the binding affinities of PU4 within the active pocket of EGFR-TK. The compound PU4 showed potent interactions with EGFR exhibiting -32.3â kJ/mol binding energy which was found best as compared to gefitinib i. e., -27.4â kJ/mol which was further validated by molecular dynamics simulations and ADMET analysis. The results of these analyses indicate that the top hits obtained from the virtual screening possess the ability to act as effective EGFR inhibitor. Therefore, it is recommended to further investigate the inhibitory potential of these identified compounds using inâ vitro and inâ vivo approaches.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Receptores ErbB/metabolismo , Simulação de Dinâmica Molecular , Purinas , Pirimidinas/farmacologia , Pirimidinas/químicaRESUMO
The newly FDA-approved drug, Axitinib, is an effective therapy against RTKs, but it possesses severe adverse effects like hypertension, stomatitis, and dose-dependent toxicity. In order to ameliorate Axitinib's downsides, the current study is expedited to search for energetically stable and optimized pharmacophore features of 14 curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione) derivatives. The rationale behind the selection of curcumin derivatives is their reported anti-angiogenic and anti-cancer properties. Furthermore, they possessed a low molecular weight and a low toxicity profile. In the current investigation, the pharmacophore model-based drug design, facilitates the filtering of curcumin derivatives as VEGFR2 interfacial inhibitors. Initially, the Axitinib scaffold was used to build a pharmacophore query model against which curcumin derivatives were screened. Then, top hits from pharmacophore virtual screening were subjected to in-depth computational studies such as molecular docking, density functional theory (DFT) studies, molecular dynamics (MD) simulations, and ADMET property prediction. The findings of the current investigation revealed the substantial chemical reactivity of the compounds. Specifically, compounds S8, S11, and S14 produced potential molecular interactions against all four selected protein kinases. Docking scores of -41.48 and -29.88 kJ/mol for compounds S8 against VEGFR1 and VEGFR3, respectively, were excellent. Whereas compounds S11 and S14 demonstrated the highest inhibitory potential against ERBB and VEGFR2, with docking scores of -37.92 and -38.5 kJ/mol against ERBB and -41.2 and -46.5 kJ/mol against VEGFR-2, respectively. The results of the molecular docking studies were further correlated with the molecular dynamics simulation studies. Moreover, HYDE energy was calculated through SeeSAR analysis, and the safety profile of the compounds was predicted through ADME studies.
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Neoplasias Colorretais , Curcumina , Humanos , Simulação de Acoplamento Molecular , Curcumina/farmacologia , Farmacóforo , Axitinibe , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Curcuma/metabolismo , Detecção Precoce de Câncer , Simulação de Dinâmica Molecular , LigantesRESUMO
Naphthalene ring is present in a number of FDA-approved, commercially available medications, including naphyrone, terbinafine, propranolol, naproxen, duloxetine, lasofoxetine, and bedaquiline. By reacting newly obtained 1-naphthoyl isothiocyanate with properly modified anilines, a library of ten novel naphthalene-thiourea conjugates (5a-5j) were produced with good to exceptional yields and high purity. The newly synthesized compounds were observed for their potential to inhibit alkaline phosphatase (ALP) and scavenge free radicals. All of the investigated compounds displayed a more powerful inhibitory profile than the reference agent, KH2PO4 particularly compound 5h and 5a exhibited strong inhibitory potential against ALP with IC50 value of 0.365 ± 0.011 and 0.436 ± 0.057 µM respectively. In addition, Lineweaver-Burk plots revealed the non-competitive inhibition mode of the most powerful derivative i.e., 5h (ki value 0.5 µM). To investigate the putative binding mode of selective inhibitor interactions, molecular docking was performed. It is recommended that future research will focus on developing selective alkaline phosphatase inhibitors by modifying the structure of the 5h derivative.
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INTRODUCTION: Alzheimer's disease is a form of dementia which affects majority of the people. It is characterized by memory loss and other cognitive function disabilities and is one of the most challenging neurodegenerative disorders to treat because of its progressive nature. The disease affects millions of people all around the world, and the number of those affected is expanding every day. In the previous study, the 4-phthalimidobenzenesulfonamide derivatives were synthesized as AChE and BChE inhibitors, and here, we were aiming to further reporting in silico studies of these compounds for efficient drug discovery process and to find out the potential lead compounds. METHODS: In silico characterization included density functional theory (DFT) studies, 3D-QSAR, ADMET properties, molecular docking, and molecular dynamic simulations. The geometries of all derivatives were optimized using B3LYP method and 6-311G basis set. RESULTS: The findings of the current study revealed that 4-phthalimidobenzenesulfonamide derivatives exhibited a reactive electronic property which is essential for anticholinesterase activity. Moreover, optimized structures were subjected to molecular docking studies with targeted protein. The compounds 2c and 2g showed excellent binding score of -37.44 and -33.67 kJ/mol with BChE and AChE, respectively, and exhibited strong binding affinity. The potent derivatives produced stable complex with amino acid residues of active pocket of both BChE and AChE. The stability of protein-ligand complexes was determined by molecular dynamic simulation studies, and results were found in correlation with molecular docking findings. CONCLUSION: Findings of the current study suggested that these derivatives are potent inhibitors of cholinesterase enzyme.
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Urease is an amidohydrolase enzyme that is responsible for fatal morbidities in the human body, such as catheter encrustation, encephalopathy, peptic ulcers, hepatic coma, kidney stone formation, and many others. In recent years, scientists have devoted considerable efforts to the quest for efficient urease inhibitors. In the pharmaceutical chemistry, the thiourea skeleton plays a vital role. Thus, the present work focused on the development and discovery of novel urease inhibitors and reported the synthesis of a set of 1-aroyl-3-[3-chloro-2-methylphenyl] thiourea hybrids with aliphatic and aromatic side chains 4a-j. The compounds were characterized by different analytical techniques including FT-IR, 1H-NMR, and 13C-NMR, and were evaluated for in-vitro enzyme inhibitory activity against jack bean urease (JBU), where they were found to be potent anti-urease inhibitors and the inhibitory activity IC50 was found in the range of 0.0019 ± 0.0011 to 0.0532 ± 0.9951 µM as compared to the standard thiourea (IC50 = 4.7455 ± 0.0545 µM). Other studies included density functional theory (DFT), antioxidant radical scavenging assay, physicochemical properties (ADMET properties), molecular docking and molecular dynamics simulations. All compounds were found to be more active than the standard, with compound 4i exhibiting the greatest JBU enzyme inhibition (IC50 value of 0.0019 ± 0.0011 µM). The kinetics of enzyme inhibition revealed that compound 4i exhibited non-competitive inhibition with a Ki value of 0.0003 µM. The correlation between DFT experiments with a modest HOMO-LUMO energy gap and biological data was optimal. These recently identified urease enzyme inhibitors may serve as a starting point for future research and development.
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Antioxidantes , Tioureia , Antioxidantes/farmacologia , Canavalia/metabolismo , Inibidores Enzimáticos/química , Simulação de Acoplamento Molecular , Espectroscopia de Infravermelho com Transformada de Fourier , Relação Estrutura-Atividade , Tioureia/química , Tioureia/farmacologia , Urease/metabolismoRESUMO
The acetophenone-based 3,4-dihydropyrimidine-2(1H)-thione was synthesized by the reaction of 4-methylpent-3-en-2-one (1), 4-acetyl aniline (2) and potassium thiocyanate. The spectroscopic analysis including: FTIR, 1H-NMR, and single crystal analysis proved the structure of synthesized compound (4), with the six-membered nonplanar ring in envelope conformation. In crystal structure, the intermolecular N-H ⯠S and C-H ⯠O hydrogen bonds link the molecule in a two-dimensional manner which is parallel to (010) the plane enclosing R22 (8) and R22 (10) ring motifs. After that, the Hirshfeld surfaces and their related two-dimensional fingerprint plots were used for thorough investigation of intermolecular interactions. According to Hirshfeld surface analysis, the most substantial contributions to the crystal packing are from H ⯠H (59.5%), H ⯠S/S ⯠H (16.1%), and H ⯠C/C ⯠H (13.1%) interactions. The electronic properties and stability of the compound were investigated through density functional theory (DFT) studies using B3LYP functional and 6-31G* as a basis set. The compound 4 displayed the high chemical reactivity with chemical softness of 2.48. In comparison to the already reported known tyrosinase inhibitor, the newly synthesized derivatives exhibited almost seven-fold better inhibition of tyrosinase (IC50 = 1.97 µM), which was further supported by molecular docking studies. The compound 4 inside the active pocket of ribonucleotide reductase (RNR) exhibited a binding energy of -19.68 kJ/mol, and with mammalian deoxy ribonucleic acid (DNA) it acts as an effective DNA groove binder with a binding energy of -21.32 kJ/mol. The results suggested further exploration of this compound at molecular level to synthesize more potential leads for the treatment of cancer.
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Monofenol Mono-Oxigenase , Ribonucleotídeo Redutases , Tionas/farmacologia , Simulação de Acoplamento Molecular , Acetofenonas/farmacologia , DNARESUMO
NIMA-related kinase7 (NEK7) plays a multifunctional role in cell division and NLRP3 inflammasone activation. A typical expression or any mutation in the genetic makeup of NEK7 leads to the development of cancer malignancies and fatal inflammatory disease, i.e., breast cancer, non-small cell lung cancer, gout, rheumatoid arthritis, and liver cirrhosis. Therefore, NEK7 is a promising target for drug development against various cancer malignancies. The combination of drug repurposing and structure-based virtual screening of large libraries of compounds has dramatically improved the development of anticancer drugs. The current study focused on the virtual screening of 1200 benzene sulphonamide derivatives retrieved from the PubChem database by selecting and docking validation of the crystal structure of NEK7 protein (PDB ID: 2WQN). The compounds library was subjected to virtual screening using Auto Dock Vina. The binding energies of screened compounds were compared to standard Dabrafenib. In particular, compound 762 exhibited excellent binding energy of -42.67 kJ/mol, better than Dabrafenib (-33.89 kJ/mol). Selected drug candidates showed a reactive profile that was comparable to standard Dabrafenib. To characterize the stability of protein-ligand complexes, molecular dynamic simulations were performed, providing insight into the molecular interactions. The NEK7-Dabrafenib complex showed stability throughout the simulated trajectory. In addition, binding affinities, pIC50, and ADMET profiles of drug candidates were predicted using deep learning models. Deep learning models predicted the binding affinity of compound 762 best among all derivatives, which supports the findings of virtual screening. These findings suggest that top hits can serve as potential inhibitors of NEK7. Moreover, it is recommended to explore the inhibitory potential of identified hits compounds through in-vitro and in-vivo approaches.
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Carcinoma Pulmonar de Células não Pequenas , Aprendizado Profundo , Neoplasias Pulmonares , Descoberta de Drogas , Detecção Precoce de Câncer , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Quinases Relacionadas a NIMARESUMO
This paper presents the developmental process of ultra-high performance concrete (UHPC), the most advanced form of concrete. The entire process exclusively utilized locally available materials. The mixes were prepared without using any specialized mixer or treatments, such as elevated pressure, etc. The primary objective of the research was to develop low-cost non-proprietary version of UHPC by optimizing both cementitious and non-cementitious materials to attain the highest levels of workability, compressive strength, flexural strength and durability. The research utilizes a trial-and-error approach, subjecting specimens to curing in both regular and heated water. The findings validate the viability of producing self-compacting UHPC with compressive strength ranging from 120 to 160 MPa, employing local materials and manufacturing methods. Raw materials and mixing sequence had a significant influence on the fresh and hardened properties of UHPC. The inclusion of steel fibers and the application of heat treatment remarkably enhanced the compressive strength. Furthermore, cost analysis revealed that this particular UHPC is only slightly over four times more expensive than conventional concrete, in contrast to commercially available UHPC, which is approximately 10 times expensive than traditional concrete.
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Rice (Oryza sativa L.) is one of the most consumed cereals that along with several important nutritional constituents typically provide more than 21% of the caloric requirements of human beings. Aflatoxins (AFs) are toxic secondary metabolites of several Aspergillus species that are prevalent in cereals, including rice. This review provides a comprehensive overview on production factors, prevalence, regulations, detection methods, and decontamination strategies for AFs in the rice production chain. The prevalence of AFs in rice is more prominent in African and Asian than in European countries. Developed nations have more stringent regulations for AFs in rice than in the developing world. The contamination level of AFs in the rice varied at different stages of rice production chain and is affected by production practices, environmental conditions comprising temperature, humidity, moisture, and water activity as well as milling operations such as de-husking, parboiling, and polishing. A range of methods including chromatographic techniques, immunochemical methods, and spectrophotometric methods have been developed, and used for monitoring AFs in rice. Chromatographic methods are the most used methods of AFs detection followed by immunochemical techniques. AFs decontamination strategies adopted worldwide involve various physical, chemical, and biological strategies, and even using plant materials. In conclusion, adopting good agricultural practices, implementing efficient AFs detection methods, and developing innovative aflatoxin decontamination strategies are imperative to ensure the safety and quality of rice for consumers.
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Aflatoxinas , Descontaminação , Contaminação de Alimentos , Oryza , Oryza/química , Oryza/microbiologia , Aflatoxinas/análise , Contaminação de Alimentos/análise , Descontaminação/métodos , Humanos , Aspergillus/metabolismo , Manipulação de Alimentos/métodos , Microbiologia de AlimentosRESUMO
The study aimed to evaluate the potential of piperidine-based 2H chromen-2-one derivatives against targeted enzymes, i.e., cholinesterase's and monoamine oxidase enzymes. The compounds were divided into three groups, i.e., 4a-m ((3,4-dimethyl-7-((1-methylpiperidin-4-yl)oxy)-2H-chromen-2-one derivatives), 5a-e (3,4-dimethyl-7-((1-methypipridin-3-yl)methoxy)-2H-chromen-2-one derivatives), and 7a-b (7-(3-(3,4-dihydroisoquinolin-2(1H)-yl)propoxy)-3,4-dimethyl-2H-chromen-2-one derivatives) with slight difference in the basic structure. The comprehensive computational investigations were conducted including density functional theories studies (DFTs), 2D-QSAR studies, molecular docking, and molecular dynamics simulations. The QSAR equation revealed that the activity of selected chromen-2-one-based piperidine derivatives is being affected by the six descriptors, i.e., Nitrogens Count, SdssCcount, SssOE-Index, T-2-2-7, ChiV6chain, and SssCH2E-Index. These descriptor values were further used for the preparation of chromen-2-one based piperidine derivatives. Based on this, 83 new derivatives were created from 7 selected parent compounds. The QSAR model predicted their IC50 values, with compound 4 k and 4kk as the most potent multi-targeted derivative. Molecular docking results exhibited these compounds as the best inhibitors; however, 4kk exhibited greater activity than the parent compounds. The results were further validated by molecular dynamic simulation studies along with the suitable physicochemical properties. These results prove to be an essential guide for the further design and development of new piperidine based chromen-2-one derivatives having better activity against neurodegenerative disorder.
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A total of 180 food borne isolates of methicillin resistant Staphylococcus aureus (MRSA) (oxacillin MICs 864 µg/ml) were used in the present study to investigate the effect of oxacillin on biofilm formation and its detachment process. Majority (98.3%) of these isolates were found to carry icaA gene. Out of 180 isolates 35.5% were identified as MRSA and 64.4% were methicillin sensitive S. aureus (MSSA). Biofilm studies by con-red agar and tube methods revealed that 57% of the MRSA isolates were biofilm producers. Polymerase chain reaction studies suggested that all of the biofilm positive MRSA isolates belong to SCCmec type IV and carry agr type II. This showed the strong association of SCCmec IV agr type II and biofilm formation in food borne MRSA. Conversely, only 13.7% of the MSSA isolates were biofilm positive and majority was found to carry agr type II. It has been noticed that oxacillin has regulatory effect on icaA expression and induce the icaA dependent polysaccharide intracellular adhesin (PIA) production and biofilm formation. This was confirmed by Real Time PCR studies of MRSA and MSSA isolates. Quantitative analysis showed that most of the MRSA isolates started biofilm formation after 24 h of incubation in the presence of sub-inhibitory concentration of oxacillin and achieved highest adhesion on glass slide after 48 h. The control in the absence of oxacillin showed slow conversion from planktonic to biofilm mode of growth (Table 1). Another novel feature of most of these biofilm producing isolates is the reduction in (Optical Density) OD, which is noticed after 48 h of incubation. Possibly, after 48 h oxacillin loses its toxicity or consumed the cells re-adapt to the planktonic state, possibly, by the activation of accessory gene regulator A (agrA) which has an important role in biofilm dispersal.
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Antibacterianos/farmacologia , Biofilmes/crescimento & desenvolvimento , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/fisiologia , Oxacilina/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Biofilmes/efeitos dos fármacos , Humanos , Staphylococcus aureus Resistente à Meticilina/genética , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/genética , Staphylococcus aureus/crescimento & desenvolvimento , Transativadores/genética , Transativadores/metabolismoRESUMO
Significant metabolic pathways have been linked to AKR1B1 and AKR1B10. These enzymes are crucial biological targets in the therapy of colon cancer. In the past several decades, drug repurposing has gained appeal as a time and cost-efficient strategy for providing new indications for existing drugs. The structural properties of the plant-based alkaloidal drugs theobromine and theophylline were examined using density functional theory (DFT) computations, where the B3LYP/SVP method was used to quantify the dipole moment, polarizability, and optimization energy. Optimized structures obtained through DFT studies were docked inside the active pocket of target proteins to evaluate their inhibitory potential. Moreover, molecular dynamic simulation provides significant insight into a dynamic view of molecular interactions. The findings of current revealed theobromine and theophylline as strong AKR1B1 and AKR1B10 inhibitors, respectively. In addition, the anti-cancer potential of theophylline and theobromine was validated by targeting various tumor proteins, i.e. NF-κB, cellular tumor antigen P53 and caspase-3 using a molecular docking approach. Theobromine was found to be strongly interacted with NF-κB and caspase-3, whereas theophylline potentially inhibited cellular tumor antigen P53. In addition, the ADMET characteristics of theobromine and theophylline were identified, confirming their drug-like capabilities. These results should open the way for further experimental validation and structure-based drug design/repurposing of AKR1B1/AKR1B10 inhibitors for the treatment of colon cancer and associated malignancies.Communicated by Ramaswamy H. Sarma.
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The NEK7 protein is required for spindle formation, cell division, and the activation of the NLRP3 inflammasome receptor. The aberrant expression of NEK7 has been implicated to the growth of metastasis and severe inflammatory conditions like rheumatoid arthritis, liver cirrhosis, and gout. An emergent target for the development of anti-cancer drugs is NEK7. In this context, the PubChem database was used to retrieve the 675 compound library and FDA-approved protein kinase inhibitors, which were then thoroughly examined via in-silico experiments. Computational studies investigated the binding orientation, electronic, and thermodynamic characteristics of drug candidates related to target protein. Drugs were investigated using density functional theory and molecular docking to find binding interactions with NEK7. Molecular dynamic simulations assessed interactions and stability of protein-ligand complex. DFT analyses showed that selected compounds maintained a significant amount of chemical reactivity in both liquid and gaseous states. Alectinib, Crizotinib, and compound 146476703 all displayed promising molecular interactions, according to molecular docking studies, with docking scores of - 32.76, - 30.54, and - 34.34 kJ/mol, respectively. Additionally, MD simulations determined the stability and dynamic characteristics of the complex over a 200 ns production run. The current study's findings indicate that the drugs Alectinib, Crizotinib, and compound 146476703 can successfully inhibit the overexpression of the NEK7 protein. To discover more potent drugs against NEK7, it is recommended to synthesize the derivatives of Alectinib and Crizotinib and carry out additional in-vitro and in-vivo studies at the molecular level.
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Proteína 3 que Contém Domínio de Pirina da Família NLR , Inibidores de Proteínas Quinases , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Quinases Relacionadas a NIMA/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Crizotinibe , Simulação de Acoplamento Molecular , ProteínasRESUMO
Aim of present study was to synthesize a novel chitosan-quercetin (CTS-QT) complex by making a carbodiimide linkage using maleic anhydride as cross-linker and to investigate its enhanced antibacterial and antioxidant activities as compare to pure CTS and QT. Equimolar concentration of QT and maleic anhydride were used to react with 100 mg CTS to form CTS-QT complex. For this purpose, three bacterial strains namely E. Coli, S. Aureus and P. Aeruginosa were used for in-vitro antibacterial analysis (ZOI, MIC, MBC, checker board and time kill assay). Later molecular docking studies were performed on protein structure of E. Coli to assess binding affinity of pure QT and CTS-QT complex. MD simulations with accelerated settings were used to explore the protein-ligand complex's binding interactions and stability. Antioxidant profile was determined by performing DPPH⢠radical scavenging assay, total antioxidant capacity (TAC) and total reducing power (TRP) assays. Delivery mechanism to CTS-QT complex was improved by synthesizing polycaprolactone containing microspheres (CTS-QT-PCL-Levo-Ms) using Levofloxacin as model drug to enhance their antibacterial profile. Resulted microspheres were evaluated by particle size, charge, surface morphology, in-vitro drug release and hemolytic profile and are all were found within limits. Antibacterial assay revealed that CTS-QT-PCL-Levo-Ms showed more than two folds increased bactericidal activity against E. Coli and P. Aeruginosa, while 1.5 folds against S. Aureus. Green colored formation of phosphate molybdate complexes with highest 85 ± 1.32% TAC confirmed its antioxidant properties. Furthermore, molecular docking and dynamics studies revealed that CTS-QT was embedded nicely within the active pocket of UPPS with binding energy greater than QT with RSMD value of below 1.5. Conclusively, use of maleic acid, in-vitro and in-silico antimicrobial studies confirm the emergence of CTS-QT complex containing microspheres as novel treatment strategy for all types of bacterial infections.Communicated by Ramaswamy H. Sarma.
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NEK7 is a NIMA related-protein kinase that plays a crucial role in spindle assembly and cell division. Dysregulation of NEK7 protein leads to development and progression of different types of malignancies including colon and breast cancers. Therefore, NEK7 could be considered as an attractive target for anti-cancer drug discovery. However, few efforts have been made for the development of selective inhibitors of NIMA-related kinase but still no FDA approved drug is known to selectively inhibit the NEK7 protein. Dacomitinib and Neratinib are two Enamide derivatives that were approved for treatment against non-small cell lung cancer and breast cancer respectively. Drug repurposing is a time and cost-efficient method for re-evaluating the activities of previously authorized medications. Thus, the present research involves the repurposing of two FDA-approved medications via comprehensive in silico approach including Density functional theory (DFTs) studies which were conducted to determine the electronic properties of the Dacomitinib and Neratinib. Afterward, binding orientation of selected drugs inside NEK7 activation loop was evaluated through molecular docking approach. Selected drugs exhibited potential molecular interactions engaging important amino acid residues of active site. The docking score of Dacomitinib and Neratinib was -30.77 and -26.78 kJ/mol, respectively. The top ranked pose obtained from molecular docking was subjected to Molecular Dynamics (MD) Simulations for investigating the stability of protein-ligand complex. The RMSD pattern revealed the stability of protein-ligand complex throughout simulated trajectory. In conclusion, both drugs displayed inhibitory efficacy against NEK7 protein and provide a prospective therapy option for malignant malignancies linked with NEK7.
RESUMO
The compounds 2a-2h containing a thiazolidinone pharmacophore were synthesized via hetrerocylization of thiosemicarbazones with dimethyl acetylenedicarboxylate. The hybrid molecules were evaluated for anticancer activity against the human cell lines MCF-7, T47D (human breast adenocarcinoma) and HeLa (cervical cancer). Compounds 2c showed effective cytotoxicity on MCF-7 and HeLa (GI50 6.40 ± 0.10 µM/mL and GI5010.30 ± 1.09 µM/mL), and compound 2d also showed effective cytotoxicity against MCF-7 and HeLa cell lines i.e., (GI50 16.60 ± 0.21 µM/mL and GI50 15.02 ± 0.14 µM/mL). These findings were comparable to cisplatin (azane;dichloroplatinum) the standard drug (GI50 13.20 ± µM/mL and 15.10 µM/mL respectively) and consequently nominated for determination of the mode of cell death. The results revealed the cytotoxic effects of 2c and 2d by induction of apoptosis in MCF-7 and HeLa cell lines. Moreover the results were further supported by the Molecular Docking which predicts the binding interactions of the best anticancer ligands with Ribonucleotide reductase (RNR), which is essential enzyme required for de-novo synthesis of DNA precursors. Molecular dynamic simulations were also performed to determine the stability of protein-ligand complex under different simulated conditions. In addition, the computational studies including DFTs, ADMET properties suggested these compounds can act as lead molecules, for the synthesis of novel drug candidates for the treatment of specific cancer and its associated malignancies.