Effects of carbamate pesticides intermediates on Escherichia coli membrane architecture: An in vitro and in silico approach

Methyl isocyanate (MIC), a low molecular weight synthetic aliphatic compound, having an isocyanate group (−NCO), has industrial application. In this study, the effects of methyl isocyanate and its mechanism on outer membrane protein of Escherichia coli were observed using experimental and computational methods. In vitro exposure of N-succinimidyl N-methylcarbamate (NSNM) a synthetic analogue of MIC on E. coli to a final concentration of 2 mM was found to affect the growth curve pattern and changes in cell morphology. Molecular docking studies of MIC and NSNM with E. coli outer membrane protein (OmpW, OmpX, OmpF OmpA), and periplasmic domain (PAL) were performed. The in-silico results revealed that outer membrane protein OmpF showed the highest negative binding energy, i.e. ∆G -4.11 kcal/mole and ∆G -3.19 kcal/mole by NSNM and MIC as compared to other proteins. Our study concludes that methyl isocyanate retains lethal toxicity which leads to cell death due to the membrane protein damage of E. coli membrane.

Identification of Natural Inhibitors Against SARS-CoV-2 Drugable Targets Using Molecular Docking, Molecular Dynamics Simulation, and MM-PBSA Approach

The present study explores the SARS-CoV-2 drugable target inhibition efficacy of phytochemicals from Indian medicinal plants using molecular docking, molecular dynamics (MD) simulation, and MM-PBSA analysis. A total of 130 phytochemicals were screened against SARS-CoV-2 Spike (S)-protein, RNA-dependent RNA polymerase (RdRp), and Main protease (Mpro). Result of molecular docking showed that Isoquercetin potentially binds with the active site/protein binding site of the Spike, RdRP, and Mpro targets with a docking score of -8.22, -6.86, and -9.73 kcal/mole, respectively. Further, MS 3, 7-Hydroxyaloin B, 10-Hydroxyaloin A, showed -9.57, -7.07, -8.57 kcal/mole docking score against Spike, RdRP, and Mpro targets respectively. The MD simulation was performed to study the favorable confirmation and energetically stable complex formation ability of Isoquercetin and 10-Hydroxyaloin A phytochemicals in Mpro-unbound/ligand bound/standard inhibitor bound system. The parameters such as RMSD, RMSF, Rg, SASA, Hydrogen-bond formation, energy landscape, principal component analysis showed that the lead phytochemicals form stable and energetically stabilized complex with the target protein. Further, MM-PBSA analysis was performed to compare the Gibbs free energy of the Mpro-ligand bound and standard inhibitor bound complexes. The analysis revealed that the His-41, Cys145, Met49, and Leu27 amino acid residues were majorly responsible for the lower free energy of the complex. Drug likeness and physiochemical properties of the test compounds showed satisfactory results. Taken together, the study concludes that that the Isoquercetin and 10-Hydroxyaloin A phytochemical possess significant efficacy to bind SARS-Cov-2 Mpro active site. The study necessitates further in vitro and in vivo experimental validation of these lead phytochemicals to assess their anti-SARS-CoV-2 potential.

Interfacial Interactions of Phosphatidylglycerol with Oligonucleotide DNA Revealed by Molecular Dynamics Method

An interaction of DNA with lipids is of great interest because of their functions. As fatty acids and lipids can specifically bind to nucleic acids forming a code sequence of the genomic DNA, it is important to study the interaction of the oligonucleotide DNA (dA)20•(dT)20 with phosphatidylglycerol by the molecular dynamics method. Molecular docking has shown that these components form a stable complex with 5.8 kcal/mole binding energy, wherein the lipid is located in the DNA minor groove. This configuration marks 354 atom groups separated by a distance less than 3.4 Ǻ. The van der Waals and hydrophobic interactions play the leading part in the DNA-phospholipid complex stabilization along with hydrogen bonds.

Identification of Potential Lead Molecules against Dibenzo[a,l]pyrene-induced Mammary Cancer through Targeting Cytochrome P450 1A1, 1A2, and 1B1 Isozymes

Cytochrome P450 (CYP) isozymes are promising therapeutic targets against dibenzo[a,l]pyrene-induced mammary cancer. Current research aims to identify potential lead molecules against mammary cancer targetting CYP1A1, 1A2, and 1B1 using ligand-based virtual screening (LBVS), molecular interactions, MD simulation, and in vitro studies. The LBVS predicted 30,500 hits, which were reduced to 400 when sifted through Lipinski RO5, and ADMET parameters. These 400 compounds were carried forward for molecular docking with the selected CYP isozymes. The ligand CHEMBL224064 (CHEMBL1), CHEMBL2420083 (CHEMBL2), and CHEMBL61745 (CHEMBL3) depicted stronger binding respectively in CYP1A1 (-10-52 kcal/mol), 1A2 (-10.82 kcal/mol), and 1B1 (-10.78 kcal/mol) in comparison to known inhibitor alpha-naphthoflavone (ANF) (-9.13 kcal/mol, -9.66 kcal/mole, and -9.67 kcal/mol respectively in CYP1A1, 1A2, and 1B1). These compounds were found stable with their respective targets during MD studies of 50 ns duration. Furthermore, (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) (MTT) and enzyme inhibition assay elucidated and validated the inhibitory potential of identified ligands against mammary carcinomas. The study reveals a significant understanding of PAH-mediated mammary cancer and its prevention.

Clinical and In-Silico study of COVID?19 patients using Thymus capitatus extract as adjuvant Therapy

Thymus capitatus extract has been considered a promise as antiviral agent against COVID‑19 viruses. We hypothesized that Thymus capitatus components may interact with key protein targets of COVID‑19 (coronavirus 2 (SARS-CoV-2) causing severe acute respiratory syndromes. Molecular docking analysis was carried out using 31 components of Thymus capitatus with SARS-CoV-2 protease enzyme (6LU7) and spike glycoprotein (6VSB). The compounds with the best normalized docking scores to protease enzyme were allo-Aromadendrene (-6.3 kcal/mole), spathulenol (-6.6 kcal/mole) and ledene (-6.8 kcal/mole). The best docking ligands for spike glycoprotein were allo-Aromadendrene (-6.6 kcal/mole), spathulenol (-6.6 kcal/mole) and ledene (-7.3 kcal/mole). All Thymus capitatus components may act synergistically to produce the therapeutic action. Thymus capitatus components may potentiate the effect of prednisolone, azithromycin and other medicines used to treat COVID-19 patients.

Molecular Docking Studies of Indolyl-Benzodioxyl-Chalcone, Pyrrolyl-Benzodioxyl- Chalcone, and Thiophenyl-Benzodioxyl-Chalcone as an Antimalarial Agent

The drug resistance condition of P. falciparum pose a major challenge in the fight against malaria. This prompts a comprehensive research in an effort to discover new drug candidates. Therefore, chalcone was modified into 24 new compounds, including indolyl-benzodioxyl-chalcone, pyrrolyl-benzodioxyl-chalcone, and thiophenyl-benzodioxyl-chalcone in the course of this study. Moreover, these compounds are commercial malaria mediciations screened for their inhibitory activity using molecular docking simulations. Subsequent results of combined indolyl-benzodioxyl-chalcone and PfDHFR-TS showed the intrinsic indolyl components produced stronger interactions referenced to pyrrolyl-benzodioxyl-chalcone, thiophenyl-benzodioxyl-chalcone, and chloroguanide. Under these circumstances, intense PfDHFR-TS-indolyl-benzodioxyl-chalcone complex was produced with lower binding affinity values (-7.32 to -8.43 kcal/mole) referenced to PfDHFR-TS-pyrrolyl-benzodioxyl-chalcone (-6.38 to -6.68 kcal/mole), PfDHFR-TS-Thiophenyl-benzodioxyl-chalcone (-6.47 to -6.52 kcal/mole), and PfDHFR-TS-chloroguanide (-6.75 kcal/mole). Furthermore, the hydrogen bond interactions developed by indolyl-benzodioxyl-chalcone (7-10) are observably similar to standard chloroguanide compounds and WR99210. These compounds also possess a binding affinity similar to WR99210 (native ligand) and are expected to be potentially anti-malarial candidates.

Molecular Docking and Dynamics Simulation Analysis of Thymoquinone and Thymol Compounds from Nigella sativa L. that Inhibit Cag A and Vac A Oncoprotein of Helicobacter pylori: Probable Treatment of H. pylori Infections

Background: Helicobacter pylori infection is accountable for most of the peptic ulcer and intestinal cancers. Due to the uprising resistance towards H. pylori infection through the present and common proton pump inhibitors regimens, the investigation of novel candidates is the inevitable issue. Medicinal plants have always been a source of lead compounds for drug discovery. The research of the related effective enzymes linked with this gram-negative bacterium is critical for the discovery of novel drug targets. Objective: The aim of the study is to identify the best candidate to evaluate the inhibitory effect of thymoquinone and thymol against H. pylori oncoproteins, Cag A and Vac A in comparison to the standard drug, metronidazole by using a computational approach. Materials and Methods: The targeted oncoproteins, Cag A and Vac A were retrieved from RCSB PDB. Lipinski’s rule and ADMET toxicity profiling were carried out on the phytoconstituents of the N. sativa. The two compounds of N. sativa were further analyzed by molecular docking and MD simulation studies. The reported phytoconstituents, thymoquinone and thymol present in N. sativa were docked with H. pylori Cag A and Vac A oncoproteins. Structures of ligands were prepared using ChemDraw Ultra 10 software and then changed into their 3D PDB structures using Molinspiration followed by energy minimization by using software Discovery Studio client 2.5. Results: The docking results revealed the promising inhibitory potential of thymoquinone against Cag A and Vac A with docking energy of -5.81 kcal/mole and -3.61kcal/mole, respectively. On the contrary, the inhibitory potential of thymol against Cag A and Vac A in terms of docking energy was -5.37 kcal/mole and -3.94kcal/mole as compared to the standard drug, metronidazole having docking energy of -4.87 kcal/mole and -3.20 kcal/mole, respectively. Further, molecular dynamic simulations were conducted for 5ns for optimization, flexibility prediction, and determination of folded Cag A and Vac A oncoproteins stability. The Cag A and Vac A oncoproteins-TQ complexes were found to be quite stable with the root mean square deviation value of 0.2nm. Conclusion: The computational approaches suggested that thymoquinone and thymol may play an effective pharmacological role to treat H. pylori infection. Hence, it could be summarized that the ligands thymoquinone and thymol bound and interacted well with the proteins Cag A and Vac A as compared to the ligand MTZ. Our study showed that all lead compounds had good interaction with Cag A and Vac A proteins and suggested them to be a useful target to inhibit H. pylori infection.

Synthesis Optimization of Guanidinium Dinitramide (GDN)

Dinitramide anion [−N(NO2)2] salt composed of resonance structure is a plausible oxidizing agents, as efficient propellant. Among them, guanidinium dinitramide (GDN) is an organic compound improving the stability against moisture, as well long term storage. An additional advantage composed guanidinium ion is the reaction efficient via the decomposed by-product during pyrognostics, maximum yield of 99%. The types of GDN (GDN-I, II, III, IV, V) were synthesized using several starting material such as guanidine acetate, chloride, carbonate, nitrate and sulfate under hydrodeprivation. In this work, the intermediates formed in these processes were closely identified and their thermal properties, and chemical structure were examined. The absorption peaks by Fourier transform infrared (FT-IR) were found guanidinium infrared frequencies (3452, 3402, 3354, 3278, 1642 cm−1) and dinitramide infrared frequencies (3208, 1570, 1492, 1416, 1337, 1179, 1000 cm−1). The activation energy of GDN samples were obtained Ea = 53.26 Kcal/mole (GDN-I), 50.94 Kcal/mole (GDN-II), 52.34 Kcal/mole (GDN-III), 62.19 Kcal/mole (GDN-IV), 55.32 Kcal/mole (GDN-V) from exothermic at over 153°C.

Ajmalicine and its Analogues Against AChE and BuChE for the Management of Alzheimer’s Disease: An In-silico Study

Background: Alzheimer's disease (AD) is the most well-known reason for disability in persons aged greater than 65 years worldwide. AD influences the part of the brain that controls cognitive and non-cognitive functions. Objective: The study focuses on the screening of natural compounds for the inhibition of AChE and BuChE using a computational methodology. Methods: We performed a docking-based virtual screening utilizing the 3D structure of AChE and BuChE to search for potential inhibitors for AD. In this work, a screened inhibitor Ajmalicine similarity search was carried out against a natural products database (Super Natural II). Lipinski rule of five was carried out and docking studies were performed between ligands and enzyme using ‘Autodock4.2’. Results: wo phytochemical compounds SN00288228 and SN00226692 were predicted for the inhibition of AChE and BuChE, respectively. The docking results revealed Ajmalicine, a prominent natural alkaloid, showing promising inhibitory potential against AChE and BuChE with the binding energy of -9.02 and -8.89 kcal/mole, respectively. However, SN00288228- AChE, and SN00226692-BuChE were found to have binding energy -9.88 and -9.54 kcal/mole, respectively. These selected phytochemical compounds showed better interactions in comparison to Ajmalicine with the target molecule. Conclusion: The current study verifies that SN00288228 and SN00226692 are more capable inhibitors of human AChE and BuChE as compared to Ajmalicine with reference to ΔG values.

Repurposing of FDA approved drugs targeting Main protease MPro for SARS-CoV-2

SARS-CoV-2 is one of the greatest pandemics in the history. There is no medicine or vaccine yet discovered to control the outbreak. The paper deals with repurposing existing drugs to control the outbreak of SARS-CoV-2 virus.Ten FDA-approved drugs namely Indinavir, Nelfinavir, Letermovir, Irinotecan, Elbasvir, Saquinavir, Darunavir, Raltegravir, Atazanavir and Amprenavir were studied. In silico methods for virtual screening of protein-ligand docking of these drugs against SARS-CoV-2 MPro was performed. The binding efficiency of the drugs against viral main protease MPro was significantly high to inhibit SARS-CoV-2.The results confirmed that Atazanavir, Nelfinavir, and Letermovir not only occupied the active site of Mpro but also showed increased binding affinity (-10.36 kcal/mole, -9.47 kcal/mole and -9.43 kcal/mole) even more than of control drugs of Lopinavir (-8.71 kcal/mole) and Ritonavir (-8.08 kcal/mole). These repurposed drugs can be used in combination or individually as an alternative approach for rapid drug discovery against SARS-CoV-2