Ascorbic Acid as an Inhibitor for SARS-CoV-2 Virus Reproduction: A Theoretical Approach

In the present study, ascorbic acid’s or Vitamin C’s influence (VC) in inhibition of SARS-CoV-2 virus reproduction was investigated. Gaussian 09 with a basis set of 6-311G (d, p), MGL tools, DSV, and LigPlus software were used. According to the Total Electron Density (TED) and Millikan charges, the active sites for adsorption were determined. Further, the docking study had clearly revealed the role of VC in inhibition of the virus reproduction in accordance with binding energy (Eb) and ligand efficiency (LE). The vitamin’s interaction with the virus’s spikes may limit its replication or provide the immune system sufficient time to recognize the infection, which enhances the possibility of producing appropriate antibodies.

Development and Validation Molecular Docking Analysis of Human serum albumin (HSA)

Background: HAS (Human Serum Albumin) is a highly water-soluble globular plasma protein, with a relative molecular weight (g/mol) of 67 KDa, consisting of 585 amino acid residues. In this study, we have investigated the interaction of the crystal structures complexed in human serum albumin at resolutions of 2.8 to 2.0: Camptothecin, 9-amino-camptothecin, Etoposide, Teniposide, Bicalutamide and Idarubicin, using a bioinformatic approach, estimated by Pyrx Virtual Screen Tool and AMDock ( AMDock, Assisted Molecular Docking). We have analyzed a validated protocol, studying several parameters, as Binding Affinity, RMSD value, Ligand Efficiency, and Inhibition constant (Ki value). Methods: Human Serum Albumin protein preparation was characterized with several programs, as Chimera, MGLTools 1.5.6, Swiss PDB Viewer Software to perform docking analysis by Autodock Vina estimated with Pyrx Software. Results: In this work, we found crystalized camptothecin, 9-amino-camptothecin and teniposide, gave excellent results for Binding Affinity, (kcal/mol), RMSD value (A ), inhibition constant Ki value (nM): -Binding Affinity of 9-amino-camptothecin (ca.-10 kcal/mol), camptothecin ( -9 kcal/mol) and teniposide ( -11 kcal/mol, -RMSD Value of 9 -amino-camptothecin (ca.1.8 A ), camptothecin (ca.2.2 A ) and teniposide (ca. 3.6 A), - Ki Value: 9 -amino-camptothecin (ca 59 nM), camptothecin ( ca 183 nM) and teniposide ( ca 9 nM), -Ligand efficiency: of 9 -amino-camptothecin(ca -0.35 kcal/mol) , camptothecin (ca -0.34 kcal/mol) and teniposide (ca -0.24 kcal/mol Conclusions: We explored the best three crystallized ligand in Human Serum Albumin. Moreover, we have observed a complete overlap, during the re-docking analysis phase, estimated by chimera Software. Therefore we have concluded that ID PDB Crystal 4L8U human serum albumin-Crystallised 9 -amino Camptothecin; ID PDB Crystal 4L9K human serum albumin- Crystallised Camptothecin and ID PDB Crystal 4L9Q human serum albumin-Crystallised teniposide be used as a possible as a reference template protein to be compared with the target protein, by Docking molecular analysis.

Docking Molecular analysis of potential Drug Paritaprevir against Mycobacterium tuberculosis (Mtb)

Background: Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis, which kills 1.8 million annually. This is an infectious disease generally affects the lungs, but can also affect other parts of the body. Mtb RNA polymerase (RNAP) is the target of the first-line antituberculosis drug Rifampin (Rif). We report first time a Potential Drug Paritaprevir against with severe infectious disease , by in Silico approach, using Autodock Vina and Autodock 4 ( or MGL Tool), estimated with Pyrx and AMDock Software, calculating three different important parameters: Binding Affinity ( kcal/mol), estimated Ki ( in nM units) and Ligand Efficiency ( L.E. in kcal/mol). After a selective analysis of over 1000 drugs, processed with Pyrx (a Virtual Screening software for Computational Drug Discovery) in the Ligand Binding site pocket of the protein ( ID PDB 5UHB chain C,DNA-directed RNA polymerase subunit beta), we noticed high values of these 3 parameters mentioned above of Paritaprevir, concluding that it could be an excellent candidate drug for this type of infection. Indeed, from the results of Autodock Vina and Autodock 4 ( or Autodock 4.2 ), implemented with lamarckian genetic algorithm, LGA, trough AMDock Software, This oral drug, approved by FDA in 2014, both by Autodock Vina and Autodock Vina 4 has excellent Binding affinity value, ca. -10.00 kcal/mol, a Ki value 40 nM and Ligand efficiency ca -0.15 kcal/mol. These results are comparable to the drug crystallized in the above-mentioned protein, currently used against TBC.

In Silico Study of Coumarins and Quinolines Derivatives as Potent Inhibitors of SARS-CoV-2 Main Protease

The pandemic that started in Wuhan (China) in 2019 has caused a large number of deaths, and infected people around the world due to the absence of effective therapy against coronavirus 2 of the severe acute respiratory syndrome (SARS-CoV-2). Viral maturation requires the activity of the main viral protease (Mpro), so its inhibition stops the progress of the disease. To evaluate possible inhibitors, a computational model of the SARS-CoV-2 enzyme Mpro was constructed in complex with 26 synthetic ligands derived from coumarins and quinolines. Analysis of simulations of molecular dynamics and molecular docking of the models show a high affinity for the enzyme (∆Ebinding between −5.1 and 7.1 kcal mol−1). The six compounds with the highest affinity show Kd between 6.26 × 10–6 and 17.2 × 10–6, with binding affinity between −20 and −25 kcal mol−1, with ligand efficiency less than 0.3 associated with possible inhibitory candidates. In addition to the high affinity of these compounds for SARS-CoV-2 Mpro, low toxicity is expected considering the Lipinski, Veber and Pfizer rules. Therefore, this novel study provides candidate inhibitors that would allow experimental studies which can lead to the development of new treatments for SARS-CoV-2.

Synthesis of Isoindoline-1,3-Dione Derivatives as Cyclooxygenase (Cox) S Inhibitors

Inflammation is the vital part of the immune system's response to injury and infection. It is the body's way of signaling the immune system to heal and repair damaged tissue. The objective of this paper is to design and synthesize a new isoindoline 1,3-dinoe derivative and investigate their selective anti inflammatory activity to COXs. As a potential anti-inflammatory compound, Isoindoline-1,3-dione derivatives were synthesized from the addition reaction of phthalimide, formaldehyde, catalytic amount of potassium hydroxide and cyclic amine in ethanol yielded the desired Isoindoline-1,3-dione compounds (ZJ1-ZJ6. 1H-NMR, ¹³C-NMR, FT-IR and elemental analysis were consistent with the assigned structures. Isoindoline-1,3-dione derivatives exhibited good inhibitory activity against the COX enzymes. To explain the result of our investigation to COX-1 and COX-2 and the selectivity of our compounds to either COX-1 or COX-2, the rationalization in COX-1, the amino group participate more effectively in binding with the ligand while in COX-2, the aryl group is more effective in binding to the ligand. The amino acetylenic compounds behave differently toward COXs from our compound. ZJ4 have shown some selective COX-1 ligand efficiency while ZJ1 promised a potent blockage and ligand efficiency toward the COX-2 enzyme which was found to be higher than the marketed drug Indomethacin and near potency score of Celecoxib. For the first time, this indicates the requirement of investigating the removal of acetylenic group in this study showed that it might be a different binding site in COXs which may result in effective compounds.

Theoretical Evaluation of Novel Thermolysin Inhibitors from Bacillus thermoproteolyticus. Possible Antibacterial Agents

The search for new antibacterial agents that could decrease bacterial resistance is a subject in continuous development. Gram-negative and Gram-positive bacteria possess a group of metalloproteins belonging to the MEROPS peptidase (M4) family, which is the main virulence factor of these bacteria. In this work, we used the previous results of a computational biochemistry protocol of a series of ligands designed in silico using thermolysin as a model for the search of antihypertensive agents. Here, thermolysin from Bacillus thermoproteolyticus, a metalloprotein of the M4 family, was used to determine the most promising candidate as an antibacterial agent. Our results from docking, molecular dynamics simulation, molecular mechanics Poisson–Boltzmann (MM-PBSA) method, ligand efficiency, and ADME-Tox properties (Absorption, Distribution, Metabolism, Excretion, and Toxicity) indicate that the designed ligands were adequately oriented in the thermolysin active site. The Lig783, Lig2177, and Lig3444 compounds showed the best dynamic behavior; however, from the ADME-Tox calculated properties, Lig783 was selected as the unique antibacterial agent candidate amongst the designed ligands.

N,N’-Dialkyl-2-Thiobarbituric acid based Sulfonamides as potential SARS-CoV-2 main protease inhibitors

An efficient methodology was developed to avail novel N,N’-dialkyl-2-thiobarbituric acid based sulfonamides S1-S4 in good to excellent yields (84-95%). The synthesized compounds S1-S4 were docked to screen their In-silico activities against two enzymes i.e. SARS-CoV-2 main protease enzyme with unliganded active site (2019-nCoV, coronavirus disease 2019, COVID-19) PDB ID: 6Y84 and SARS-CoV-2 Mpro PDB ID: 6LU7. Furthermore, some In-silico physicochemical and physicokinetic properties were evaluated using OSIRIS property explorer online, molinspiration property calculator, ADMET property calculator and GUSAR to assess these compounds as potential candidates as lead compounds for the quest of SARS- CoV-2 main protease inhibitors. Molecular docking analyses of the synthesized compounds predicted that compound S3 is more potent as SARS-CoV-2 main protease inhibitor with binding energy -11.65 Kcal/mol in comparison to reference inhibitor N3 (-10.95 Kcal/mol), whereas, compounds S1, S2 and S4 recorded comparable binding energies -9.89 Kcal/mol, -10.84 Kcal/mol and -10.94 Kcal/mol with reference inhibitor N3, however much better than remdesivir (-9.85 Kcal/mol). In case of SARS-CoV-2 Mpro, all compounds S1-S4 with docking energy values as -7.28, -8.38, -8.31 and -7.34 Kcal/mol were found potent in comparison to reference inhibitor N3 (-6.31 Kcal/mol) as well as remdesivir (-6.33 Kcal/mol). Ligand efficiency values against the target SARS-CoV-2 proteins as well as α-glucosidase and DNA-(apurinic or apyrimidinic site) lyase inhibition results of these newly synthesized compounds were also found promising.

Design, synthesis and biological evaluation of 1H-pyrrolo[2,3-b]pyridine derivatives as potent fibroblast growth factor receptor inhibitors

Discovery of a new class of 1H- pyrrorole [2,3-b]pyridine FGFR inhibitors with high ligand efficiency.