Structure and Evolution of the Small Blue Proteins
René Lontie in Copper Proteins and Copper Enzymes, 1984
A stereo-pair showing the poplar Pc structure is given in Figure 4. The molecule forms a slightly flattened barrel 4.0 nm high and 2.8 × 3.2 nm wide. The peptide chain folds into eight strands roughly parallel to the long axis. Seven of these are in correct conformation for β-structure, while the fifth middle strand is irregular and even contains a turn of approximate helix. The core of the molecule is hydrophobic and made up of six of the seven phenylalanine side chains. On the surface of the molecule a negative patch of six carboxylates and a hydrophobic patch on the top of the molecule formed by seven residues widely spread in the linear structure are noteworthy. The copper site at the top of the molecule consists of three liganding side-chains — Cys-89, His-92, and Met-97 — from the turn between strands 7 and 8, and a histidine side-chain (His-39) from strand 4.
Finding a Target
Nathan Keighley in Miraculous Medicines and the Chemistry of Drug Design, 2020
The reaction profile in Figure 2.1 illustrates how the energy difference between the substrate and the transition state at the top of the curve, which is the activation energy, is lowered in formation of an enzyme-substrate complex. Less energy is required for the reaction to proceed, so more encounters between the enzyme and the substrate will lead to a successful reaction, hence rate is increased. The mechanism for hydrolysis of a peptide bond explains how the catalytic process operates. The negative charge of the carboxylate pushes electron density onto the electronegative oxygen atom of the water molecule, making it a strong nucleophile. Meanwhile, the electronegative nitrogen atom of a second amino acid residue pulls electron density from the C=O bond, creating a partial positive charge on the carbon, making it very susceptible to nucleophilic attack from the oxygen lone pair of electrons, hence the reaction proceeds quickly.
Coupled Mass Spectrometic—Chromatographic Systems
Steven H. Y. Wong, Iraving Sunshine in Handbook of Analytical Therapeutic Drug Monitoring and Toxicology, 2017
The revolutionary aspect of ES is that multiply charged ions could be efficiently formed from polymers and biological molecules with masses greater than 100,000 Da. If 20 charges exist on a molecule of mass 10,000, the m/z would be 500, well within the m/z range of quadrupole mass analyzers. The fact that a charge distribution is generally observed on these macromolecules gives the analyst multiple estimates of its molecular mass, resulting in mass estimates with precision better than 1%. Thus, it is easy to detect the difference between recombinant human growth hormone and native growth hormone (molecular weight = 22,120 vs. 22,260), which differ by a single methionine residue or the microheterogeneity of glycopeptides differing by a single monosaccharide. Although the analysis of proteins provides new opportunities for the toxicologist in understanding mechanisms of toxicity, the major impact of ES is in the efficient, gentle ionization of labile small molecules. Because ion formation occurs from the liquid state, the best response is observed for ionic compounds. Adjustment of the solution pH can produce positive ions for carboxylates and even sulfates. It is not unusual to observe adducts with ammonia, sodium, or potassium if these ions are present in the mobile phase.
Discovery of a fragment hit compound targeting D-Ala:D-Ala ligase of bacterial peptidoglycan biosynthesis
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Matic Proj, Martina Hrast, Gregor Bajc, Rok Frlan, Anže Meden, Matej Butala, Stanislav Gobec
Compound 3 was then additionally docked using extra-precision Glide (Glide XP)21 and also redocked using QM-Polarized Ligand Docking (QPLD) protocol22 that generates partial charges on the ligand atoms by quantum mechanical calculations on the ligand in the field of the receptor. This accounts for the polarisation of the charges on the ligand by the receptor environment, and redocking with these new charges can lead to improved docking accuracy. The QPLD pose showed a difference of 2.54 Å from the original pose, mainly due to the m-tolyl ring flip (Figure 2(E)). Based on the putative binding mode, the carboxylic acid mimics the phosphate groups of ATP that coordinate Mg2+ ions (Figure 2(D,E)). As shown in Table 4, the electrostatic term (XP Electro) from Coulombic and metal interactions contributes the most, followed by XP Zpotr, which denotes a reward for ligand atoms placed in a favourable electrostatic environment of the protein, and XP PhobEn, a reward for hydrophobic enclosure. Thus, the appropriately positioned carboxylate group is mainly responsible for successful binding.
MRP4 is responsible for the efflux transport of mycophenolic acid β-d glucuronide (MPAG) from hepatocytes to blood
Published in Xenobiotica, 2021
Joseph Berthier, Mehdi Benmameri, François-Ludovic Sauvage, Gabin Fabre, Benjamin Chantemargue, Hélène Arnion, Pierre Marquet, Patrick Trouillas, Nicolas Picard, Franck Saint-Marcoux
The four ligands (MPA, MPAG, MK571 and ibuprofen) were parameterized using both the antechamber package (Wang et al., 2006) and the GAFF2 force field (Wang et al., 2004). The parameters for the glucuronide moiety of MPAG were obtained from the GLYCAM 06-j force field (Kirschner et al., 2008). According to its low pKa value, the COOH moiety was systematically deprotonated to study the carboxylate, predominant, form. Atomic partial charges were derived from a RESP (restrained electrostatic potential) fitting with R.E.D.III (Cornell et al., 1993) based on DFT-B3LYP/cc-pVDZ calculations performed in a diethylether implicit solvent. The ff14SB (Maier et al., 2015) and the lipid17 (Gould et al., 2018) (force fields were used for the protein and the lipids, respectively. The TIP3P model was used for water (Jorgensen & Madura, 1983; Vassetti et al., 2019).
Liposome–ligand conjugates: a review on the current state of art
Published in Journal of Drug Targeting, 2020
İpek Eroğlu, Mamudu İbrahim
This is the most frequently used linkage in terms of engineering liposome conjugates. Ester bond is formed when hydroxyl group of a molecule reacts (sometimes with the help of succinic acid as linkers) with carboxylic acid group of the liposomes or vice versa [100]. Because of the unreactive nature of carboxyl groups (due to low nucleophilic property), reactants such as carbonyl diimidazole are used to modify these carboxyl groups to make room for ester linkages. Carbonyl diimidazole is an active carbonylating agent consisting of two acylimidazole-leaving groups that react with carboxylic acids to generate N-acylimidazoles of high reactivity. The active carboxylate resulting from this reaction is then positioned to bond with hydroxyl groups through ester linkages [64]. This bond is usually meant to be broken by esterase enzymes through the process of hydrolysis; but then several factors including adjacent groups (e.g. bromide) and spacers may influence the cleavage process [101,102]. Guo and Szoka [103] utilised diortho ester to successfully synthesise low pH-sensitive PEG-diortho ester-distearoyl glycerol conjugate (POD). Distearoyl glycerol containing two saturated hydrocarbon side chains is coupled to the diortho ester (3,9-diethyl-2,4,8,10-tetraoxaspiro[5]undecane) in order to facilitate the anchoring of PEG2000 into lipid bilayers. The formed liposome conjugate was found to be stable up to 12 h at neutral pH, but degraded at pH 5 to release the payload, and thus found to be suitable for application in tumour targeting.
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