Preface

Small-molecule crystal structures as a structural basis for drug design

Correlation between small-molecule X-ray structures and biological systems.

Intermolecular interactions around functional groups in crystals: data for modeling the binding of drugs to biological macromolecules

An overview is given of the directionality of selected intermolecular interactions. These data are obtained from crystal structure determinations and can be used for modeling drug-macromolecule interactions.

Zinc-directed inhibitors for zinc proteinases

Crystallogtaphic, inhibition and electrostatic studies with carbexygeptidase A present further details about the role of the Zn atom and other active-site groups in substrate binding and catalysis of zinc proteinases. These details combined with model compound studies suggest a rational approach for specific inhibitor design for this enzyme family which is based on zinc binding and its particular coordination preferences.

Mastering the LORE of protein structure

A detailed description of software for the exploitation of known structural information in the modeling of protein structures is presented.

Glucose analogue inhibitors of glycogen phosphorylase: from crystallographic analysis to drug prediction using GRID force-field and GOLPE variable selection

Several glucose analogue inhibitors of glycogen phosphorylase have been studied in crystallographic, kinetic and 3D QSAR experiments. Comparison of the N-methylacetylglucopyranosyl amine with the analogous C-methylamide derivative showed a fivetold improvement in Ki and a 200-fold improvement compared with glucose.

Binding of the antiviral drug WIN51711 to the sabin strain of type 3 poliovirus: structural comparison with drug binding in rhinovirus 14

High-resolution crystal structures of complexes of peliovirus and rhinovirus with the antiviral compound disoxaril (WIN5l7ll) are compared.

WIN51711-resistant mutants of poliovirus type 3: capsid residues important in uncoating functions

Capsid-binding drugs that inhibit the first stage in picornaviral uncoating were used to select drug-resistant mutants of peliovirus type 3. Such mutants focus attention on parts of the capsid liable to have important functions in viral uncoating.

Structures of four methyltetrazole-containing antiviral compounds in human rhinovirus serotype 14

The structures of four novel capsid-binding antipicornaviral compounds are determined in human rhinovirus 14. These structures are used to provide a better understanding of drug-design issues within the capsid-binding pocket of rhinoviruses.

Benzoic acid inhibitors of influenza virus neuraminidase

Aromatic inhibitors of influenza virus neuraminidase were designed using X-ray crystal structures. The success of this iterative strategy could be applied in other drug-design targets.

Comparative X-ray structures of the major binding protein for the immunosuppressant FK506 (tacrolimus) in unliganded form and in complex with FK506 and rapamycin

The structure of FKBPl2 is reported for the first time in its unliganded form, and in complex with 18 inhibitors. Analysis of these structures suggests that FKBP12 is locally flexible.

Design, synthesis and structure of non-macrocyclic inhibitors of FKBP12, the major binding protein for the immunosuppressant FK506

Simple, non-macrocyclic inhibitors bind FKBPl2 as tightly as FK506 and potently inhibit the peptidyl prolyl isomerase activity of that enzyme. The structure of one of these in complex with FKBPI2 is presented.

Structure-based design of inhibitors of purine nucleoside phosphorylase

Structure-based drug-design techniques have been utilized to design and synthesize novel and potent inhibitors of purine nucleoside phosphorylase.

Calculation of relative binding affinities of purine nucleoside phosphorylase inhibitors

Experimentally measured binding constants of inhibitors to purine nucleoside phosphorylase compared with calculations using X-PLOR, DelPhi and SoftDock give mixed results.

Molecular dynamics and structure-based drug design for predicting non-natural nonapeptide binding to a class I MHC protein

From the crystal structure of a class I MHC protein, non-natural peptides have been successfully designed as high-affinity ligands for the target protein.

Active-site mimetic inhibition of thrombin

The structures of two mimetic inhibitor complexes of thrombin have been determined. One is based on a conformationally restricted bicyclic β-twin while the other mimics two different active-site binding modes.

Correlation of binding affinities with non-bonded interaction energies of thrombin-inhibitor complexes

Evaluation of several empirical modeling protocols for estimating the binding between thrombin and 35 inhibitors showed an optimal predictive value when during the energy minimization the enzyme was constrained and electrostatics were scaled down.

A comparison of two independently determined structures of trypano­thione reductase from Crithidia fasciculata

Trypanothione reductase is a target for chemotherapy of trypanosomal infection. A detailed comparison of two crystal forms provides a consensus template for drug design.

Refined 3.2 Å structure of glycosomal holo glyceraldehyde phosphate de­hydrogenase from Trypanosoma brucei brucei

The structure of the hologlyceraldehyde 3-phosphate dehydrogenase was solved at 3.2 Å resolution from Laue data by a combination of molecular replacement, density modification and refmement by simulated annealing including non-crystallographic symmetry constraints and restraints. The three-dimensional structure of this enzyme is described and compared to the model of the enzyme from Bacillus stearothermophilus.

Crystallographic and thermodynamic comparison of structurally diverse molecules binding to streptavidin

Crystallographic structure and thermodynamic binding parameters are compared for three structural classes of streptavidin ligand including d-biotin, 2-[(4'-hydroxyphenyl)-azo] benzoate and the peptide NH2 -Phe-Ser-His-Pro-Gln-Asn-Thr-COOH. Descriptions of these structural and thermodynamic observations emphasize the diversity of potential strategies for improving ligand affinity.

Structure-based analysis of inhibitor binding to Ht-d

A theoretical study was performed on the structure of both the native and inhibited metalloproteinase Ht-d solved at 2.0 Å resolution. The study suggests the structural link between Ht-d and mammalian metalloproteinases, contributing to the understanding of the mechanism of natural and synthetic inhibitors binding to metalloproteinases.

Crystallization and preliminary structure of porcine aldehyde reductase–NADPH binary complex

In the crystal structure of porcine aldehyde reductase-NADPH binary complex NADPH is held in place by a loop. A conformational change is necessary for the association and dissociation of NADPH.