Mechanism-Based Inactivation of Cytochromes by Furan Epoxide: Unraveling the Molecular Mechanism

Drugs carrying an unsaturated CC center (such as furans) form reactive epoxide metabolites and cause irreversible mechanism-based inactivation (MBI) of cytochrome P450 (CYP450) activity, through covalent modification of amino acid residues. Though this reaction is confirmed to take place in the active site of CYPs, the details of the reactions of furan (epoxidation and epoxide ring opening), the conditions under which MBI may occur, the residues involved, the importance of the heme center, etc. have yet to be explored. A density functional theory (DFT) study was carried out (i) to elucidate the reaction pathways for the generation of furan epoxide metabolite from furan ring by the model oxidant <b>Cpd I</b> (iron­(IV)-oxo heme-porphine radical cation, to mimic the catalytic domain of CYPs) and (ii) to explore different reactions of the furan epoxide metabolite. The energy profiles of the competitive pathways and the conditions facilitating MBI of CYPs by the reactive epoxide metabolite are reported. The rate-determining step for the overall metabolic pathway leading to MBI was observed to be the initial epoxidation, requiring ∼12 kcal/mol under the enzymatic conditions. The covalent adducts (inactivator complexes) are highly stable (∼−46 to −70 kcal/mol) and may be formed due to the reaction between furan epoxide and nucleophilic amino acid residues such as serine/threonine, preferably after initial activation by basic amino acids

Nanotechnology for COVID-19: Therapeutics and Vaccine Research.

The current global health threat by the novel coronavirus disease 2019 (COVID-19) requires an urgent deployment of advanced therapeutic options available. The role of nanotechnology is highly relevant to counter this "virus" nano enemy. Nano intervention is discussed in terms of designing effective nanocarriers to counter the conventional limitations of antiviral and biological therapeutics. This strategy directs the safe and effective delivery of available therapeutic options using engineered nanocarriers, blocking the initial interactions of viral spike glycoprotein with host cell surface receptors, and disruption of virion construction. Controlling and eliminating the spread and reoccurrence of this pandemic demands a safe and effective vaccine strategy. Nanocarriers have potential to design risk-free and effective immunization strategies for severe acute respiratory syndrome coronavirus 2 vaccine candidates such as protein constructs and nucleic acids. We discuss recent as well as ongoing nanotechnology-based therapeutic and prophylactic strategies to fight against this pandemic, outlining the key areas for nanoscientists to step in

Nanotechnology for COVID-19: Therapeutics and Vaccine Research.

The current global health threat by the novel coronavirus disease 2019 (COVID-19) requires an urgent deployment of advanced therapeutic options available. The role of nanotechnology is highly relevant to counter this "virus" nano enemy. Nano intervention is discussed in terms of designing effective nanocarriers to counter the conventional limitations of antiviral and biological therapeutics. This strategy directs the safe and effective delivery of available therapeutic options using engineered nanocarriers, blocking the initial interactions of viral spike glycoprotein with host cell surface receptors, and disruption of virion construction. Controlling and eliminating the spread and reoccurrence of this pandemic demands a safe and effective vaccine strategy. Nanocarriers have potential to design risk-free and effective immunization strategies for severe acute respiratory syndrome coronavirus 2 vaccine candidates such as protein constructs and nucleic acids. We discuss recent as well as ongoing nanotechnology-based therapeutic and prophylactic strategies to fight against this pandemic, outlining the key areas for nanoscientists to step in

Knoevenagel/Tandem Knoevenagel and Michael Adducts of Cyclohexane-1,3-dione and Aryl Aldehydes: Synthesis, DFT Studies, Xanthine Oxidase Inhibitory Potential, and Molecular Modeling

Xanthine oxidase (XO) plays a crucial role in the formation of uric acid by oxidative hydroxylation of purines. Herein, we report the design and synthesis of Knoevenagel/tandem Knoevenagel and Michael adducts of cyclohexane-1,3-dione and aryl aldehydes as nonpurine XO inhibitors derived from naturally occurring scaffolds. Density functional theory calculations highlighted the reaction pathways and reasoned the formation of tandem Knoevenagel and Michael adducts. The synthetics were assessed for their XO inhibitory potential, and among them, four compounds (1b, 1g, 2b, and 3a) were found to possess best IC50 values in the range of 3.66–4.98 μM. Interestingly, Knoevenagel adducts exhibited a competitive-type inhibition, whereas tandem Knoevenagel and Michael adducts produced a noncompetitive mode of inhibition. The compounds were capable of reducing the H2O2 levels induced by XO, both in normal and cancer cells with no significant cytotoxicity. Molecular modeling studies highlighted the role of interactions of compounds with residual amino acids of the XO active site and also corroborated with the observed structure–activity relationship

<i>In silico</i> binding mechanism prediction of benzimidazole based corticotropin releasing factor-1 receptor antagonists by quantitative structure activity relationship, molecular docking and pharmacokinetic parameters calculation

<p>Despite the various research efforts toward the treatment of stress-related disorders, the drug has not yet launched last 20 years. Corticotropin releasing factor-1 receptor antagonists have been point of great interest in stress-related disorders. In the present study, we have selected benzazole scaffold-based compounds as corticotropin releasing factor-1 antagonists and performed 2D and 3D QSAR studies to identify the structural features to elucidating the binding mechanism prediction. The best 2D QSAR model was obtained through multiple linear regression method with <i>r</i>² value of .7390, <i>q</i>² value of .5136 and pred_<i>r</i>² (predicted square correlation coefficient) value of .88. The contribution of 2D descriptor, T_2_C_1 was 60% (negative contribution) and 4pathClusterCount was 40.24% (positive contribution) in enhancing the activity. Also 3D QSAR model was statistically significant with <i>q</i>² value of .9419 and <i>q</i>²_se (standard error of internal validation) value of .19. Statistical parameters results prove the robustness and significance of both models. Further, molecular docking and pharmacokinetic analysis was performed to explore the scope of investigation. Docking results revealed that the all benzazole compounds show hydrogen bonding with residue Asn283 and having same hydrophobic pocket (Phe286, Leu213, Ile290, Leu287, Phe207, Arg165, Leu323, Tyr327, Phe284, and Met206). Compound B14 has higher activity compare to reference molecules. Most of the compounds were found within acceptable range for pharmacokinetic parameters. This work provides the extremely useful leads for structural substituents essential for benzimidazole moiety to exhibit antagonistic activity against corticotropin releasing factor-1 receptors.</p

THPdb: Database of FDA Approved Peptide and Protein Therapeutics

THPdb is a manually curated database of Food and Drug Administration (FDA) approved therapeutic peptide and proteins. The text file contain all the data curated in THPdb

A schematic representation of distribution of therapeutic peptides and proteins based on disease, function/ mode of activity, route of administration, and pharmacological class.

<p>A schematic representation of distribution of therapeutic peptides and proteins based on disease, function/ mode of activity, route of administration, and pharmacological class.</p

Representative screen shots of THPdb demonstrating the flow of information after submission of a query in simple search page.

<p>Representative screen shots of THPdb demonstrating the flow of information after submission of a query in simple search page.</p