Binding Energy ΔG Research Articles

Molecular docking insights into nuclear factor Y (NF-Y) transcription factor and pyrabactin resistance 1 (PYL) receptor proteins reveal abiotic stress regulation in finger millet

Finger Millet (Eleusine coracana - (L.) Gaertn), is an important nutraceutical crop with the potential for imparting food and nutritional security. These plants have a comparatively higher tolerance for several abiotic stresses like drought, salinity, and heat. Several players including Transcription Factor (TF) like Nuclear Factor Y (NF-Y) might be associated with this enhanced level of tolerance. Further, it is unclear how phytohormones like Abscisic acid (ABA) regulate the expression of NF-Y, whether in ABA-dependent or ABA-Independent pathway. The interaction of PYL (Pyrabactin resistance1-like) receptor proteins with Nuclear Factor Y (NF-Y) Transcription Factor in the presence of phytohormones like abscisic acid (ABA) provides one insight related to the enhanced tolerance towards abiotic stresses under ABA-dependent signaling in finger millet crop. A total of three PYL receptors of finger millet designated as EcPYL1, EcPYL5, and EcPYL9 were retrieved in the finger millet genome. These receptors were modeled through the SWISS-MODEL using templates 5gwo and 3wg8 and docked with ABA. The best-docked protein-ligand complex PYL5-ABA (binding energy ΔG ​= ​-8.8 kcal mol-1) was found to be most stable at the 50ns MD simulation study. Further protein-protein interaction between PYL5 and NF-YA2/B3/C1 sub-family members showed a good interaction. This clearly indicates the possibility of the NF-Y-PYL module in the ABA transduction pathway, which performs a crucial role in the expression of stress-responsive genes. These studies reveal the intricate relationship between the ABA, PYL receptors of finger millet, and NF-Y transcription factor in regulating the stress-responsive genes and provide an insight into the abiotic stress tolerance mechanisms, which can be targeted for crop improvement.

Albendazole repurposing on VEGFR-2 for possible anticancer application: In-silico analysis.

Drug repurposing is the finding new activity of the existing drug. Recently, Albendazole's well-known antihelmintic has got the attention of an anticancer drug. Plausible evidence of the interaction of Albendazole with one of the types of tyrosine kinase protein receptor, vascular endothelial growth factor receptor-2 (VEGFR-2) is still not well understood. Inhibition of the VEGFR-2 receptor can prevent tumor growth. The current study investigated the interaction of Albendazole with VEGFR-2.It was found that the said interaction exhibited potent binding energy ΔG = -7.12 kcal/mol, inhibitory concentration (Ki) = 6.04 μM, and as positive control comparison with standard drug (42Q1170A) showed ΔG = -12.35 kcal/mol and Ki = 881 μM. The key residue Asp1046 was formed involved hydrogen bonding with Albendazole. The molecular dynamics simulation study revealed the stable trajectory of the VEGFR-2 receptor with Albendazole bound complex having significant high free energy of binding as calculated from Molecular Mechanics Generalized Born and Surface Area study ΔG = -42.07±2.4 kcal/mol. The binding energy is significantly high for greater stability of the complex. Principal component analysis of molecular docking trajectories exhibited ordered motion at higher modes, implying a high degree of VEGFR-2 and Albendazole complex stability as seen with the standard drug 42Q. Therefore, the current work suggests the role of Albendazole as a potent angiogenesis inhibitor as ascertained by its potential interaction with VEGFR-2. The findings of research will aid in the future development of Albendazole in anticancer therapy.

In silico and in vitro investigation of dual targeting Prima-1MET as precision therapeutic against lungs cancer

This study emphasizes the explorations of binding of Prima-1MET with two targets, p53 a tumor suppressor protein, and tyrosine kinase of epidermal growth factor receptor. In silico investigations reveal that Prima-1MET showed robust binding with both targets. Molecular docking simulations demonstrated the binding affinity of Prima-1MET with p53 and tyrosine kinase was found to be −38.601 kJ/mol and −38.976 kJ/mol. In addition, the stability of Prima-1MET was explored by molecular dynamics simulation. Prima-1MET attains stability in the binding site of the respective protein till the simulation period is over. Moreover, the free binding energy ΔG bind was calculated by the molecular mechanics Poisson Boltzmann surface area method. The ΔG bind of Prima-1MET with tyrosine kinase was found to be −58.585 ± 0.327 kJ/mol and with p53 it was −35.910 ± 0.335 kJ/mol. Next, cytotoxicity of the Prima-1MET was evaluated using multiple cancer cell lines and the IC50 value were ranging between 4.5 and 30 μM. The cell death was identified by apoptosis assay. Further, the p53 and tyrosine kinase expression was monitored using immunofluorescence techniques, it was found Prima-1MET induces the expression of p53 protein and mimics the level of tyrosine kinase oncogenic target. Also, reactive oxygen species (ROS) and membrane potential activity of Prima-1MET was evaluated by using a lung cancer cell line. A significant decrease in intracellular ROS was observed and resulted in disruption of mitochondrial transmembrane potential. This study uncovers the underlying mechanism of Prima-1MET and could be helpful to design further leads against lung cancers. Communicated by Ramaswamy H. Sarma

Characterization of Orange Peel Extract and Its Potential Protective Effect against Aluminum Chloride-Induced Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder without a cure. Hence, developing an effective treatment or protective agent is crucial for public health. The present study aims to characterize orange peel extract (OPE) through in vitro and in silico studies. Furthermore, it examines the protective effect of OPE against experimentally-induced Alzheimer's disease in rats. The total phenolic and flavonoid content of OPE was 255.86 ± 1.77 and 52.06 ± 1.74 (mg/100 g), respectively. Gallic acid, the common polyphenol in OPE detected by HPLC was 3388.60 μg/100 g. OPE antioxidant IC50 was 67.90 ± 1.05, 60.48 ± 0.91, and 63.70 ± 0.30 by DPPH, ABTS and Hydroxyl radical scavenging activity methods, respectively. In vitro anti-acetylcholinesterase (AChE) IC50 was 0.87 ± 0.025 mg/mL for OPE and 2.45 ± 0.001 mg/mL for gallic acid. Molecular docking analysis for human AChE (4EY7) with donepezil, gallic acid, and acetylcholine showed binding energy ΔG values of -9.47, -3.72, and -5.69 Kcal/mol, respectively. Aluminum chloride injection (70 mg/Kg/day for 6 weeks) induced Alzheimer's-like disease in male rats. OPE (100 and 200 mg/kg/d) and gallic acid (50 mg/kg/d) were administered orally to experimental animals for 6 weeks in addition to aluminum chloride injection (as protective). OPE was found to protect against aluminum chloride-induced neuronal damage by decreasing both gene expression and activity of acetylcholinesterase (AChE) and a decrease in amyloid beta (Aβ42) protein level, thiobarbituric acid-reactive substances (TBARS), and nitric oxide (NO), and increased reduced glutathione (GSH) level and activity of the antioxidant enzymes in the brain tissues. Additionally, gene expressions for amyloid precursor protein (APP) and beta secretase enzyme (BACE1) were downregulated, whereas those for presinilin-2 (PSEN2) and beta cell lymphoma-2 (BCL2) were upregulated. Furthermore, the reverse of mitochondrial alternation and restored brain ultrastructure might underlie neuronal dysfunction in AD. In conclusion, our exploration of the neuroprotective effect of OPE in vivo reveals that OPE may be helpful in ameliorating brain oxidative stress, hence protecting from Alzheimer's disease progression.

Compounds Isolated from Lawsonia inermis L. Collected in Vietnam and Evaluation of Their Potential Activity Against the Main Protease of SARS-CoV-2 Using In silico Molecular Docking and Molecular Dynamic Simulation

Since late 2019 to early 2020, an outbreak caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has become a worldwide health emergency due to its rapid infection and mortality of millions of people around the world. As the main protease Mpro or 3CLpro produced by the virus plays an important role in coronavirus survival and proliferation, it becomes an excellent drug target to identify COVID-19 inhibitors. Lawsonia inermis L. (henna) is a medicinal plant that has been used for a long time for the treatment of many fungal and bacterial infections. In the search for new anti-COVID agents from medicinal plants, we report the results of our study into the potential inhibition of Mpro by the compounds isolated from the extracts of L. inermis roots and leaves using molecular docking and molecular dynamics simulation. The molecular modeling results showed that all isolated compounds bonded spontaneously into the catalytic pockets of Mpro with binding energies <0. The docking and calculated pharmacokinetic results of the compounds (1-3, 6-8) were similar to and even better than those of the commercial COVID-19 inhibitor remdesivir. In particular, the triterpenoid glycoside suavissimoside R1 (8) showed the best binding to SARS-CoV Mpro, with the lowest binding energy ΔG and IC50,calc. values of −8.19 kcal/mol and 0.98 μM, respectively. Furthermore, the calculations of ADMET (absorption, distribution, metabolism, excretion, and toxicity) showed that it had the lowest toxicity, with a predicted LD50 value of 3320 mg/kg. These triterpenoids are worthy of further study to evaluate their actual bioactivity against SARS-CoV-2 in vitro and in vivo in the hope of contributing valuable scientific data for natural resources for the development novel drug formulations for either the prevention or treatment of COVID-19.

Discovery of natural products to block SARS-CoV-2 S-protein interaction with Neuropilin-1 receptor: A molecular dynamics simulation approach.

Neuropilin-1 (NRP1) is a widely expressed cell surface receptor protein characterized by its pleiotropic function. Recent reports highlighted NRP1 as an additional entry point of the SARS-CoV-2 virus, enhancing viral infectivity by interacting with the S-protein of SARS-CoV-2. The ubiquitous distribution and mechanism of action of NRP1 enable the SARS-CoV-2 virus to attack multiple organs in the body simultaneously. Therefore, blocking NRP1 is a potential therapeutic approach against SARS-CoV-2 infection. The current study screened the South African natural compounds database (SANCDB) for molecules that can disrupt the SARS-CoV-2 S protein-NRP1 interaction as a potential antiviral target for SARS-CoV-2 cellular entry. Following excessive screening and validation analysis 3-O-Methylquercetin and Esculetin were identified as potential compounds to disrupt the S-protein-NRP1 interaction. Furthermore, to understand the conformational stability and dynamic features between NRP1 interaction with the selected natural products, we performed 200 ns molecular dynamics (MD) simulations. In addition, molecular mechanics-generalized Born surface area (MM/GBSA) was utilized to calculate the free binding energies of the natural products interacting with NRP1. 3-O-methylquercetin showed an inhibitory effect with binding energies ΔG of −25.52 ± 0.04 kcal/mol to NRP1, indicating the possible disruption of the NRP1-S-protein interaction. Our analysis demonstrated that 3-O-methylquercetin presents a potential antiviral compound against SARS-CoV-2 infectivity. These results set the path for future functional in-vitro and in-vivo studies in SARS-CoV-2 research.

Synthesis, characterization, in vitro biological evaluation and molecular docking studies of newly synthesized mononuclear lanthanum(III) complexes of N,N'-bis(2-aminoethyl)oxamide and phenanthroline bases

Four lanthanum(III) complexes were newly synthesized using the ligand N,N'-bis(2-aminoethyl)oxamide (1) and phenanthroline bases [La(oxae)2(NO3)2](NO3) (2) [La(oxae)(bpy)](NO3)3 (3), [La(oxae)(phen)](NO3)3 (4) and [La(oxae)2(dppz)](NO3)3 (5) and characterized by 1H-NMR, IR, UV–Visible spectroscopic analyses, ESI-Mass spectrometric measurements, molar conductivities, and cyclic voltammetric measurements. Complex 2 was found to be 1:1 electrolyte and complexes 3, 4 and 5 were 1:3 electrolytes. The redox ehavior of the complexes was confirmed by cyclic voltammetry. The interactions of 1 and its complexes (2, 3, 4 and 5) with calf thymus DNA (CT-DNA) were studied by UV–Visible absorption spectroscopy, cyclic voltammetric studies, viscosity measurements and molecular docking studies. The studies confirmed the highest binding propensity for complex 5 (Kb = 2.26 × 106 ± 7) in the reduced state through the intercalation method. Molecular docking studies revealed that complex 5 was found to bind strongly with the DNA molecule due to intercalation with a more negative binding energy ΔG = - 8.6 kcal/mol having an association constant (Ka) = 0.892 µM. The oxidative cleavage of SC pUC19 DNA by La(III) complexes was confirmed by the Agarose gel electrophoresis method. Of all the compounds tested, complex 5 exhibited the highest cleavage ability (94%) in the presence of H2O2 in the major groove region. The MTT assay revealed the highest antiproliferative activity of complex 5 against MCF-7 cell lines at IC50 value is 21.86 µM. The complexes have been tested for antibacterial activities wherein at 50 µg mL−1, complex 5 inhibits the growth of K. pneumonia and at 100 µg mL−1, ligand oxae (1) and its complex 2 were active against E. coli and K. pneumonia; complex 4 inhibited the growth of E. coli, K. pneumonia and B. subtilis. The antioxidant activities showed that complex 2 had the highest chelation ability towards Fe2+.

DESIGN AND SYNTHESIS OF NOVEL 1,2,3–TRIAZOLE SCAFFOLDS: BIOLOGICAL ACTIVITY AND MOLECULAR DOCKING STUDIES

The final targets are established by different types of functional groups on aryl azides with terminal alkynes of pefloxacin via click chemistry in conventional and microwave irradiation conditions. A series of novel derivatives are characterized by proton, carbon nuclear magnetic resonance technique and mass spectral techniques. From screening antibacterial results the 5c, 5d, 5e, 5f and 5g exhibited outstanding activity against Gram-positive and Gram-negative microorganisms compared to CPF. All the title compounds were subjected to molecular docking prediction and compounds 5h, 5a, 5g possesses the highest binding energy ΔG= –8.12, –7.61, –7.26 Kcal/mol, hydrogen bonding amino acid interactions Val40, Asp83, Lys93, Tyr23, Arg28 with the active site of Topoisomerase-IV from S. pneumoniae (4KPE). Further investigation, these compounds were evaluated to their molecular properties prediction by Molinspiration and Molsoft

Novel Pyrimidinone Linked 1,2,3-Triazole Scaffolds as Anti-Microbial and Antioxidant Agents: Synthesis, In-vitro and In-silico Studies

The present study states the synthesis of a novel series of pyrimidinone linked 1,2,3-triazole scaffolds by click chemistry method. Further, the synthesized compounds were evaluated for their antimicrobial studies against S. aureus and S. pneumoniae. Among the synthesized compounds, almost all compounds demonstrated significant antimicrobial activity against S. aureus, S. pneumoniae, E.coli and P. aeruginosa, as evident from the zone of inhibition resulted. In addition, synthesised compounds were screened for their antioxidant activity by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay method. Furthermore, computational study was performed to understand the interactions between synthesised compounds with dehydrosqualene synthase of Staphylococcus aureus (PDB ID: 2ZCS) and few Compound revealed the highest binding energies ΔG = -9.5, -9.8, and -10.1 Kcal/mol.

Novel heterocyclic 1,3,4-oxadiazole derivatives of fluoroquinolones as a potent antibacterial agent: Synthesis and computational molecular modeling.

Design and synthesis of novel series of 1,3,4-oxadiazoles containing FQs derivatives and screened their antibacterial, antimycobacterial properties. The synthesized compounds were characterized by different spectral techniques like IR, 1H NMR, 13C NMR, mass and elemental analysis. The results of the antimicrobial activity and compounds 6d, 6b, 6e, 6f and 6a demonstrated potent antibacterial activities with zone of inhibition of 42, 36, 37, 34 and 30mm against S. aureus, E. faecalis, S. pneumoniae, E. coli and K. pneumoniae, respectively. 1,3,4-Oxadiazole derivatives 6a, 6b, 6g were showed excellent antimycobacterial activity against M. smegmatis H37Rv with MICs 22.35, 16.20, 20.28µg/mL, respectively. FQs 6d and 6b exhibited highest hydrogen bonding interactions with Asp83 (3.11 A˚), Ser80 (2.15 A˚) Asp27 (σ-σ), Arg87 (Π-Π), Arg87 (Π-Π), Ser80 (σ-σ), Ala84 (σ-σ) and binding energies ΔG = - 6.41, - 6.97kcal/mol with active site of topoisomerase-IV from S. pneumoniae [4KPE]. We performed a computational investigation of compounds 6a-j for their absorption, distribution, metabolism and excretion (ADME) properties by using the Molinspiration, Molsoft toolkits. The ligands 6f, 6d and 6b reveal the highest pharmacokinetic properties and possess maximum drug-likeness model score 1.59, 1.46 and 1.23, respectively.

Antioxidant and anti-acetylcholinesterase potential of artichoke phenolic compounds

The present study focused on the biochemical evaluation of artichoke extract, furthermore, in vitro and in silico evaluation its potential for inhibition of acetylcholinesterase activity. The total phenolic, flavonoids, triterpenoids, tannins, and sulfide polysaccharides content were 193.63, 0.038, 71.43, 13.49, and 115.612 μg/g. (B 2) content was 60.95 μg/g, (B 9) was 6.85 μg/g, retinol (A) was 0.248422 μg/g, and (B 12) was 6.07 μg/g. Benzoic acid, ellagic acid, and caffeine were 589.91, 573.07, and 382.03 μg/100g. IC 50 values of ellagic acid, benzoic acid, caffeine, extract, and donepezil had of 16.97, 26.0, 27.28, 31.04, and 133 μg/mL. In In vitro assay; caffeine exhibited a significant noncompetitive inhibition of acetylcholinesterase (AChE) with IC 50 of 1.013 mg/mL. ellagic acid and extract exhibited competitive inhibition with IC50 of 1.927 and 5.705 mg/mL. Donepezil exhibited mixed modes of inhibition with IC50 of 0.0034 mg/mL, but benzoic acid did not exhibit any anti-AChE. In silico molecular docking of human AChE (4EY7) with donepezil, caffeine, ellagic acid, and acetylcholine showed binding energy ΔG values of −9.47, −6.07, −9.39, and −5.69 Kcal/mol, respectively. Accordingly, the current study emphasized significant of antioxidant and anti-acetylcholinesterase potential of artichoke extract and related phenolic compounds which might take the attention of scientists to explore a neuroprotective effect of artichoke extract and its promising effect towards Alzheimer disease.

Design, Synthesis and Molecular Docking Studies of Novel Pyrazole Benzimidazole Derivatives as Potent Antibacterial Agents

A novel series of pyrazole benzimidazole derivatives were synthesized and the structure of the final targets 4a-h were confirmed by IR, Mass, 13C NMR and 1H NMR spectral analysis. The new pyrazole core with imidazole and benzimidazoles derivatives were evaluated for in vitro antibacterial, antifungal activity against six bacterial strains significantly. In dispersion, 4c, 4f and 4g had the highest antibacterial activities on these microorganisms Bacillus subtilis B29, Escherichia coli E266, with zone of inhibition 21, 19 and 19 mm, respectively. Compounds 4a, 4c, 4h shows good antifungal activity against A. niger, Fusarium oxysporum fungal strains. Further, molecular docking for protein ligands interactions was performed using the crystal structure of C(30) carotenoid dehydrosqualene synthase from Staphylococcus aureus complexed with bisphosphonate BPH-700. Among the final compounds 4e, 4g and 4h show highest binding energy ΔG = -7.89, -7.48 and -7.08 Kcal/mol, respectively and amino acid interactions Lys273, Asp27.

Universal Kinetics of the Onset of Cell Spreading on Substrates of Different Stiffness

When plated onto substrates, cell morphology and even stem-cell differentiation are influenced by the stiffness of their environment. Stiffer substrates give strongly spread (eventually polarized) cells with strong focal adhesions and stress fibers; very soft substrates give a less developed cytoskeleton and much lower cell spreading. The kinetics of this process of cell spreading is studied extensively, and important universal relationships are established on how the cell area grows with time. Here, we study the population dynamics of spreading cells, investigating the characteristic processes involved in the cell response to the substrate. We show that unlike the individual cell morphology, this population dynamics does not depend on the substrate stiffness. Instead, a strong activation temperature dependence is observed. Different cell lines on different substrates all have long-time statistics controlled by the thermal activation over a single energy barrier ΔG ≈ 18 kcal/mol, whereas the early-time kinetics follows a power law ∼t5. This implies that the rate of spreading depends on an internal process of adhesion complex assembly and activation; the operational complex must have five component proteins, and the last process in the sequence (which we believe is the activation of focal adhesion kinase) is controlled by the binding energy ΔG.

Synthesis of stable benzimidazole derivatives bearing pyrazole as anticancer and EGFR receptor inhibitors

A new series of benzimidazole linked pyrazole derivatives were synthesized by cyclocondensation reaction through one-pot multicomponent reaction in absolute ethanol. All the synthesized compounds were tested for their in vitro anticancer activities on five human cancer cell lines including MCF-7, HaCaT, MDA-MB231, A549 and HepG2. EGFR receptor inhibitory activities were carried out for all the compounds. Majority of the compounds showed potent antiproliferative activity against the tested cancer cell lines. Compound 5a showed the most effective activity against the lungs cancer cell lines (IC50 = 2.2 µM) and EGFR binding (IC50 = 0.97 µM) affinity as compared to other members of the series. Compound 5a inhibited growth of A549 cancer cells by inducing a strong G2/M phase arrest. In addition, same compound inhibited growth of A549 cancer cells by inducing apoptosis. In molecular docking studies compound 5a was bound to the active pocket of the EGFR (PDB 1M17) with five key hydrogen bonds and two π-π interaction with binding energies ΔG = −34.581 Kcal/mol.

In silico pharmacokinetic and molecular docking studies of small molecules derived from Indigofera aspalathoides Vahl targeting receptor tyrosine kinases.

Angiogenesis is the formation of new blood vessels from preexisting vascular network that plays an important role in the tumor growth, invasion and metastasis. Anti-angiogenesis targeting tyrosine kinases such as vascular endothelial growth factor receptor 2 (VEGFR2) and platelet derived growth factor receptor β (PDGFRβ) constitutes a successful target for the treatment of cancer. In this work, molecular docking studies of three bioflavanoid such as indigocarpan, mucronulatol, indigocarpan diacetate and two diterpenes namely erythroxydiol X and Y derived from Indigofera aspalathoides as PDGFRβ and VEGFR2 inhibitors were performed using computational tools. The crystal structures of two target proteins were retrieved from PDB website. Among the five compounds investigated, indigocarpan exhibited potent binding energy ΔG = -7.04 kcal/mol with VEGFR2 and ΔG = -4.82 with PDGFRβ compared to commercially available anti-angiogenic drug sorafenib (positive control). Our results strongly suggested that indigocarpan is a potent angiogenesis inhibitor as ascertained by its potential interaction with VEGFR2 and PDGFRβ. This hypothesis provides a better insight to control metastasis by blocking angiogenesis.

Beta-cyclodextrin host-guest complexes probed under thermodynamic equilibrium: thermodynamics and AFM force spectroscopy.

The rupture forces of individual host-guest complexes between beta-cyclodextrin (beta-CD) heptathioether monolayers on Au(111) and several surface-confined guests were measured in aqueous medium by single molecule force spectroscopy using an atomic force microscope. Anilyl, toluidyl, tert-butylphenyl, and adamantylthiols (0.2-1%) were immobilized in mixed monolayers with 2-mercaptoethanol on gold-coated AFM tips. For all guests and for all surface coverages, the force-displacement curves measured between the functionalized tips and monolayers of beta-CD exhibited single, as well as multiple, pull-off events. The histograms of the pull-off forces showed several maxima at equidistant forces, with force quanta characteristic for each guest of 39 +/- 15, 45 +/- 15, 89 +/- 15, and 102 +/- 15 pN, respectively. These force quanta were independent of the loading rate, indicating that, because of the fast complexation/decomplexation kinetics, the rupture forces were probed under thermodynamic equilibrium. The force values followed the same trend as the free binding energy Delta G degrees measured for model guest compounds in solution or on beta-CD monolayers, as determined by microcalorimetry and surface plasmon resonance measurements, respectively. A descriptive model was developed to correlate quantitatively the pull-off force values with the Delta G degrees of the complexes, based on the evaluation of the energy potential landscape of tip-surface interaction.