Ester bond hydrolysis of membrane phospholipids by Phospholipase A2 and consequent release of fatty acids are the initiating steps of inflammation. It is proposed in this study that the inhibition of phospholipase A2 is one of the ways to control inflammation. Investigations are carried out to identify the mode of inhibition of phospholipase A2 by the n‐hexadecanoic acid. It may help in designing of specific inhibitors of phospholipase A2 as anti‐inflammatory agents. The enzyme kinetics study proved that n‐hexadecanoic acid inhibits phospholipase A2 in a competitive manner. It was identified from the crystal structure at 2.5 Å resolution that the position of n‐hexadecanoic acid is in the active site of the phospholipase A2. The binding constant and binding energy have also been calculated using Isothermal Titration Calorimetry. Also, the binding energy of n‐hexadecanoic acid to phospholipase A2 was calculated by in silico method and compared with known inhibitors. It may be concluded from the structural and kinetics studies that the fatty acid, n‐hexadecanoic acid, is an inhibitor of phospholipase A2, hence, an anti‐inflammatory compound. The inferences from the present study validate the rigorous use of medicated oils rich in n‐hexadecanoic acid for the treatment of rheumatic symptoms in the traditional medical system of India, Ayurveda.
Since its first report in December 2019 from China, the COVID-19 pandemic caused by the beta-coronavirus SARS-CoV-2 has spread at an alarming pace infecting about 5.59 million, and claiming the lives of more than 0.35 million individuals across the globe. The lack of a clinically approved vaccine or drug remains the biggest bottleneck in combating the pandemic. Drug repurposing can expedite the process of drug development by identifying known drugs which are effective against SARS-CoV-2. The SARS-CoV-2 main protease is a promising drug target due to its indispensable role in viral multiplication inside the host. In the present study an E-pharmacophore hypothesis was generated using a crystal structure of the viral protease in complex with an imidazole carbaximide inhibitor. Drugs available in the superDRUG2 database were used to identify candidate drugs for repurposing. The hits obtained from the pharmacophore based screening were further screened using a structure based approach involving molecular docking at different precisions. The binding energies of the most promising compounds were estimated using MM-GBSA. The stability of the interactions between the selected drugs and the target were further explored using molecular dynamics simulation at 100 ns. The results showed that the drugs Binifibrate and Bamifylline bind strongly to the enzyme active site and hence they can be repurposed against SARS-CoV-2. However, U.S Food and Drug Administration have withdrawn Binifibrate from the market as it was having some adverse health effects on patients.
The serine protease thrombin proteolytically activates blood coagulation factor XIII by cleavage at residue Arg 37 ; factor XIII in turn cross-links fibrin molecules and gives mechanical stability to the blood clot. The 2.0-Å resolution x-ray crystal structure of human ␣-thrombin bound to the factor XIII-(28 -37) decapeptide has been determined. This structure reveals the detailed atomic level interactions between the factor XIII activation peptide and thrombin and provides the first high resolution view of this functionally important part of the factor XIII molecule. A comparison of this structure with the crystal structure of fibrinopeptide A complexed with thrombin highlights several important determinants of thrombin substrate interaction. First, the P1 and P2 residues must be compatible with the geometry and chemistry of the S1 and S2 specificity sites in thrombin. Second, a glycine in the P5 position is necessary for the conserved substrate conformation seen in both factor XIII-(28 -37) and fibrinopeptide A. Finally, the hydrophobic residues, which occupy the aryl binding site of thrombin determine the substrate conformation further away from the catalytic residues. In the case of factor XIII-(28 -37), the aryl binding site is shared by hydrophobic residues P4 (Val 34 ) and P9 (Val 29 ). A bulkier residue in either of these sites may alter the substrate peptide conformation.The serine protease thrombin plays a central role in the blood coagulation process (1, 2). It proteolytically activates blood coagulation and plasma factors such as factor V, factor VIII, factor XIII, and protein C (3). Its proteolytic activity is also responsible for catalyzing the conversion of fibrinogen to fibrin (4) by the cleavage of fibrinopeptides A and B from the N termini of the fibrinogen ␣ and  chains, respectively. In addition, thrombin is the most potent stimulator of platelet aggregation (5). Thrombin achieves this diverse yet specific recognition of substrates with a deep active site cleft and by exploiting an apolar binding site near the catalytic residues as well as an anion binding exosite distant from the active site cleft (6).Crystal structures of ␣-thrombin complexed to a number of natural and synthetic inhibitors have been studied in detail and characterized to near atomic resolution (for example, see . These structures have provided a wealth of information about the interactions between inhibitors and enzyme. However, more limited knowledge about the atomic level interactions between substrate and thrombin comes mainly from the crystal structures of thrombin bound to fibrinopeptide A. Structures of human and bovine ␣-thrombin bound to the Nterminal peptide of the fibrinogen ␣-chain (15,16) show that the C-terminal region of the peptide runs anti-parallel to the Ser 214 -Glu 217 segment of thrombin and that the arginine at the cleavage site occupies the S1 specificity pocket. The N-terminal region of the peptide adopts a compact ␣-helical conformation, folding back toward the active site cleft to bring the hydrop...
Bisphenol-A (BPA) is a primary monomer in polycarbonate plastics and epoxy resins. BPA may be released into the environment following its formation via hydrolysis of ester bonds of the polymers. It has been detected in human plasma, placenta, amniotic fluid, amniotic chord, urine and saliva. BPA disrupts normal cell function by acting as an estrogen agonist as well as an androgen antagonist. The present study was carried out to investigate whether BPA can bind to human glucocorticoid receptor (GR) and elucidate its mode of interaction. BPA has been successfully docked in silico into the ligand binding site of GR using the program Discovery Studio 2.0. The structure has been compared with other agonist and antagonist bound structures of GR. It is found that the mode of interactions and binding energy of BPA were similar to that of DEXA and cortisol, two known agonists of GR. This reveals that BPA can bind to GR as an agonist. Hence, BPA may produce biological effects similar to that produced by glucocorticoids.
The structures of a new crystal form of ribonuclease A and its low-humidity variant, each containing two crystallographically independent molecules, have been determined and refined. A detailed comparison of these structures with those of the other known crystal forms of the enzyme, which have different packing arrangements and solvent composition, leads to a meaningful delineation of the rigid and flexible regions of the protein molecule and the nature of its plasticity. Many of the water molecules which are common to all the structures are involved in bridging different regions of the protein molecule, thus emphasizing the role of water in stabilizing the tertiary structure. The analysis of the structures shows that for a given N or O atom, the level of hydration increases with accessible surface area, but levels off at an area of about 10 A2. Generally, the hydration level tends to drop when the area increases beyond about 20 A2. This drop correlates with an increase in the displacement parameter. The analysis also suggests that the van der Waals radii and probe radius normally used in accessible surface area calculations are not appropriate for dealing with all situations.
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