Discovery of a Highly Selective Glycogen Synthase Kinase‐3 Inhibitor (PF‐04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging

Glycogen synthase kinase‐3 (GSK‐3) regulates multiple cellular processes in diabetes, oncology, and neurology. N‐(3‐(1H‐1,2,4‐triazol‐1‐yl)propyl)‐5‐(3‐chloro‐4‐methoxyphenyl)oxazole‐4‐carboxamide (PF‐04802367 or PF‐367) has been identified as a highly potent inhibitor, which is among the most selective antagonists of GSK‐3 to date. Its efficacy was demonstrated in modulation of tau phosphorylation in vitro and in vivo. Whereas the kinetics of PF‐367 binding in brain tissues are too fast for an effective therapeutic agent, the pharmacokinetic profile of PF‐367 is ideal for discovery of radiopharmaceuticals for GSK‐3 in the central nervous system. A ¹¹C‐isotopologue of PF‐367 was synthesized and preliminary PET imaging studies in non‐human primates confirmed that we have overcome the two major obstacles for imaging GSK‐3, namely, reasonable brain permeability and displaceable binding.     

Application of Shannon-like diversity measures to cell-based chemistry spaces

The use of multi-dimensional “chemistry spaces” to represent large compound collections has become widespread in pharmaceutical research. In such spaces compounds are treated as points. Points in close proximity represent similar compounds, while distant points represent dissimilar compounds. Assessing the diversity of a compound collection, thus, is tantamount to characterizing the distribution of points in chemistry space. To facilitate many procedures such as selecting subsets of compounds for screening, for compound acquisition and designing combinatorial libraries, chemistry spaces have been partitioned into sets of non-overlapping, multi-dimensional cells, which are generated by dividing each axis into a number of equal-sized bins. This leads to a lattice of (N_bins)^N_dim{(N_{bins})^{N_{\rm dim}}} cells, where N _bins is the number of bins on each axis and N _dim is the dimensionality of the space. One diversity measure that is typically used in cell-based chemistry spaces is identical in form to Shannon entropy, D_Ncpd^cpd{D_{N_{cpd}}^{cpd}} A normalized measure of this Shannon entropy given by, D_rel^cpd{D_{rel}^{cpd}} enables comparison between compound collections that occupy different number of occupied cells. Although D_rel^cpd{D_{rel}^{cpd}} characterizes the uniformity and “spreadout” of the corresponding compound collection, it treats cells as positionally independent. Some of the positional information lost can be recaptured by another diversity measure, which is also related in form to Shannon entropy. This new measure D_Nbin^cell (l){D_{N_{bin}}^{cell} (\lambda)} characterizes the distribution of occupied cells along each axis of chemistry space. The normalized measure á D_rel^cell ñ{\left\langle {D_{rel}^{cell}}\right\rangle} over all axes is given then by the average. Examples illustrating the applicability of these two Shannon-like measures to compound collections are presented.     

An information-theoretic characterization of partitioned property spaces

A methodology, derived by analogy to Shannon’s information-theoretic theory of communication and utilizing the concept of mutual information, has been developed to characterize partitioned property spaces. A family of non-intersecting subsets that cover the “universe” of objects represents a partitioned property space. Each subset is thus an equivalence class. A partition and it’s associated equivalence classes can be generated using any one of a number of procedures including hierarchical and non-hierarchical clustering, direct approaches using rough set methods, and cell-based partitioning, to name a few. Thus, partitioned property spaces arise in many instances and represent a very large class of problems. The approach is based on set-valued mappings from equivalence classes in one partition to those in another and provides a coarse-grained means for comparing property spaces. From these mappings it is possible to compute a number of Shannon entropies that afford calculation of mutual information, which represents that amount of information shared by two partitions of a set of objects. Taking the ratio of the mutual information with the maximum possible mutual information yields a quantity that measures the similarity of the two partitions. While the focus in this work is directed towards small sets of objects the approach can be extended to many more classes of problems that can be put into a similar form, which includes many types of cheminformatic and biological problems. A number of scenarios are presented that illustrate the concept and indicate the broader class of problems that can be handled by this method.     

Distinctive attributes of β-lactam target proteins in Acinetobacter baumannii relevant to development of new antibiotics

Multi-drug-resistant forms of the Gram-negative pathogen Acinetobacter baumannii are an emerging threat to human health and further complicate the general problem of treating serious bacterial infections. Meeting this challenge requires an improved understanding of the relationships between the structures of major therapeutic targets in this organism and the activity levels exhibited against it by different antibiotics. Here we report the first crystal structures of A. baumannii penicillin-binding proteins (PBPs) covalently inactivated by four β-lactam antibiotics. We also relate the results to kinetic, biophysical, and computational data. The structure of the class A protein PBP1a was solved in apo form and for its covalent conjugates with benzyl penicillin, imipenem, aztreonam, and the siderophore-conjugated monocarbam MC-1. It included a novel domain genetically spliced into a surface loop of the transpeptidase domain that contains three conserved loops. Also reported here is the first high-resolution structure of the A. baumannii class B enzyme PBP3 in apo form. Comparison of this structure with that of MC-1-derivatized PBP3 of Pseudomonas aeruginosa identified differences between these orthologous proteins in A. baumannii and P. aeruginosa. Thermodynamic analyses indicated that desolvation effects in the PBP3 ligand-binding sites contributed significantly to the thermal stability of the enzyme-antibiotic covalent complexes. Across a significant range of values, they correlated well with results from studies of inactivation kinetics and the protein structures. The structural, biophysical, and computational data help rationalize differences in the functional performance of antibiotics against different protein targets and can be used to guide the design of future agents.     

Solvent dependent study of carbonyl vibrations of 3‐phenoxybenzaldehyde and 4‐ethoxybenzaldehyde by Raman spectroscopy and ab initio calculations

A Raman spectroscopy investigation of the carbonyl stretching vibrations of 3‐phenoxybenzaldehye (3Phbz) and 4‐ethoxybenzaldeheyde (4Etob) was carried out in binary mixtures with different polar and nonpolar solvents. The purpose of this study was twofold: firstly, to describe the interaction of the carbonyl groups of two solute molecules in terms of a splitting in the isotropic and anisotropic components and secondly, to analyze their spectroscopic signatures in a binary mixture. Changes in wavenumber position, variation in the anisotropic shift and full width half maximum were investigated for binary mixtures with different mole fractions of the reference systems. In binary mixtures, the observed increase in wavenumber with solvent concentration does not show linearity, indicating the significant role of molecular interactions on the occurrence of breaking of the self‐association of the solute. In all the solvents, a gradual decrease in the anisotropic shift reflects the progressive separation of the coupled oscillators with dilution. Γ_i(η_c), 3Phbz—solvent mixtures, exhibit a gradual decrease with decrease in the concentration of the solute which is an evidence on the influence of micro viscosity on linewidth. For 4Etob, the carbonyl stretching vibration shows two well‐resolved components in the Raman spectra, attributed to the presence of two distinct carbonyl groups: hydrogen‐bonded and free carbonyl groups. The intensity ratio of the carbonyl stretching vibration of these two types of carbonyl groups is studied to understand the dynamics of solute/solvent molecules owing to hydrogen bond interactions. Ab initio calculations were employed for predicting relevant molecular structures in the binary mixtures arising from intermolecular interactions, and are related to the experimental results. Copyright © 2009 John Wiley & Sons, Ltd.     

Epilogue to the Gerald Maggiora Festschrift: a tribute to an exemplary mentor,colleague, collaborator,and innovator

Journal of Computer-Aided Molecular Design - In May 2022, JCAMD published a Special Issue in honor of Gerald (Gerry) Maggiora, whose scientific leadership over many decades advanced the fields of...