China
Africa
Explore chapters and articles related to this topic
The Chemistry and Biology of Lipooligosaccharides: The Endotoxins of Bacteria of the Respiratory and Genital Mucosae
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
J. McLeod Griffiss, Herman Schneider
Sialylation provides an additional, and distal, carboxylate. If the molecule’s minimum energy requirements are better met by a hydrogen bond between the sialic acid carboxylate and PEA than by one between Kdo and PEA, as seems likely, the former would replace the latter. Similarly, the sialic acid carboxylate is free to form an electronegative box, either with an adjacent NANA residue or with a Kdo acidic function. A NANA-Kdo carboxylate cavity would be expected to preferentially attract different cations than those that are attracted by Kdo-Kdo carboxylates. Gonococci that have been exogenously sialylated no longer can absorb lytic IgM from human sera even though they continue to have gangliosyl LOS epitopes (20). Thus, sialylation can alter epitope expression without masking terminal glycose moieties.
The Application of Fragment-based Approaches to the Discovery of Drugs for Neglected Tropical Diseases
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Christina Spry, Anthony G. Coyne
Crystals of L. major coproporphyrinogen III oxidase, an enzyme involved in porphyrin biosynthesis, were soaked with 66 different fragment cocktails. Co-crystal structures were obtained for two fragments each from different cocktails (Table 2). Interestingly, one of the two fragment hits, cyclopentyl acetate, was observed to bind at three positions within the active site. In the same structure, one molecule of acetate (co-purified with the enzyme) was also bound. The four carboxylates contributed by the three fragment molecules and the acetate molecule were predicted to occupy the binding sites of the four carboxylates of the natural substrate coproporphyinogen-III.
Reactivities of Amino Acids and Proteins with Iodine
Published in Erwin Regoeczi, Iodine-Labeled Plasma Proteins, 2019
(Interesting in this context is the observation that eight carboxylate groups can be liberated from ovalbumin on denaturation at different pH values with 2.59 M guanidine-HCl.196) Lowering the pH disrupts the hydrogen bond because the carboxylate becomes protonated.193,195
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.
In silico prediction of post-translational modifications in therapeutic antibodies
Published in mAbs, 2022
Asp isomerization is sensitive to temperature and the dielectric constant of the solvent. At neutral pH, a high dielectric constant for solvents increases the pKa of Asp, which increases the concentration of the carboxylic acid (COOH) form of the Asp side chain. The COOH form is more reactive and prone to isomerization than the carboxylate form (COO−).39 High temperatures can also accelerate the rate of isomerization reactions. Moreover, flanking residues, ionization state, and higher-order structure also influences isomerization.40 For example, the risk of isomerization is highest for Asp residues within random coils due to structural flexibility and higher solvent exposure.41 The risk of isomerization also differs for different CDR loops. Asp isomerization at liable motifs is more likely with the CDR H3, H2, and L1 loops.42
Non-specific binding of compounds in in vitro metabolism assays: a comparison of microsomal and hepatocyte binding in different species and an assessment of the accuracy of prediction models
Published in Xenobiotica, 2022
Iain Gardner, Mandy Xu, Chunyan Han, Yi Wang, Xingjin Jiao, Masoud Jamei, Hiba Khalidi, Peter Kilford, Sibylle Neuhoff, Roz Southall, David B. Turner, Helen Musther, Barry Jones, Simon Taylor
Although some of the methods for determining binding in metabolism incubations can be run in high throughput formats (96-well), computational methods have been described to predict the binding to save time particularly early in the drug discovery/development process (Gao et al. 2010). These include lipophilicity-based models from Austin ((Austin et al. 2002), called Austin Model in the current paper), Hallifax and Houston ((Hallifax and Houston 2006) called Hallifax-Houston Model) and Turner ((Turner et al. 2006), called Turner-Simcyp Model). The Austin and Hallifax-Houston models use a relationship between logP and fraction unbound for neutral and basic compounds but use logD for acidic compounds. Abraham and Austin (Abraham and Austin 2012) showed that carboxylate anions bind about 18-times less to microsomes than the corresponding protonated carboxylic acid but binding of protonated bases bind to almost the same extent as neutral compounds providing a mechanistic explanation for these empirical findings. The details of the Turner-Simcyp Model have been presented in abstract form but the model has not been published previously (Turner et al. 2006). The approach and datasets used to develop this model have been described in this paper.