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In previous work, the second author and M\"uller determined the function $c(a)$ giving the smallest dilate of the polydisc $P(1,1)$ into which the ellipsoid $E(1,a)$ symplectically embeds. We determine the function of two variables $c_b(a)$ giving the smallest dilate of the polydisc $P(1,b)$ into which the ellipsoid $E(1,a)$ symplectically embeds for all integers $b \geqslant 2$. It is known that for fixed $b$, if $a$ is sufficiently large then all obstructions to the embedding problem vanish except for the volume obstruction. We find that there is another kind of change of structure that appears as one instead increases $b$: the number-theoretic "infinite Pell stairs" from the $b=1$ case almost completely disappears (only two steps remain), but in an appropriately rescaled limit, the function $c_b(a)$ converges as $b$ tends to infinity to a completely regular infinite staircase with steps all of the same height and width., Comment: 61 pages, 12 figures

The enzyme human NAD(P)H quinone oxidoreductase-1 (NQO1), which is overexpressed in several types of tumor cell, is considered a design target for cancer therapeutics. We identify new coumarin-based competitive inhibitors of NQO1, one of which is nanomolar. Using computational docking and molecular dynamics, we obtain insights into the structural basis of inhibition. Selected inhibitors were then assessed for off-target effects associated with dicoumarol and were found to have differing effects on superoxide formation and mitochondrial respiration. A comparison of NQO1 inhibition and off-target effects for dicoumarol and its derivatives suggests that the ability of dicoumarol to kill cancer cells is independent of NQO1 inhibition, that cellular superoxide production by dicoumarol does not seem linked to NQO1 inhibition but may be related to mitochondrial decoupling, and that superoxide does not appear to be a major determinant of cytotoxicity. Implications are discussed for NQO1 inhibition as an anticancer drug design target and superoxide generation as the dicoumarol-mediated mechanism of cytotoxicity.

This paper describes the application of PRO_LEADS to the flexible docking of ligands into crystallographically derived enzyme structures that are assumed to be rigid. PRO_LEADS uses a Tabu search methodology to perform the flexible search and an empirically derived estimate of the binding affinity to drive the docking process. The paper tests the extent to which the assumption of a rigid enzyme compromises the accuracy of the results. All-pairs docking experiments are performed for three enzymes (thrombin, thermolysin and influenza virus neuraminidase) based on six or more ligand-enzyme crystal structures for each enzyme. In 76% of the cases, PRO_LEADS can successfully identify the correct ligand conformation as the lowest energy configuration when the enzyme structure is derived from that ligand's crystal structure, but the methodology only docks 49% of the cases successfully when the ligand is docked against enzyme crystal structures derived from other ligands. Small movements in the enzyme structure lead to an under-prediction in the energy of the correct binding mode by up to 14 kJ/mol and in some cases this under-prediction can lead to the native mode not being recognised as the lowest energy solution. The type of movements responsible for mis-docking are: the movement of sidechains as a result of changes in C alpha position; the movement of sidechains without changes in C alpha position; the movement of flexible portions of main chains to facilitate the formation of hydrogen bonds; and the movement of metal atoms bound to the enzyme active site. The work illustrates that the assumption of a rigid active site can lead to errors in identification of the correct binding mode and the assessment of binding affinity, even for enzymes which show relatively small shift in atomic positions from one ligand to the next. A good docking code, such as PRO_LEADS, can usually dock successfully if there is induced fit in relatively rigid enzymes but there remains the need to develop improved strategies for dealing with enzyme flexibility. The work implies that treatments of enzyme flexibility which focus only on sidechain rotations will not deal with the critical shifts responsible for mis-docking of ligands in thrombin, thermolysin and neuraminidase. The paper demonstrates the utility of all pairs docking experiments as a method of assessing the effectiveness of docking methodologies in dealing with enzyme flexibility.

ECH capacities give obstructions to symplectically embedding one symplectic four-manifold with boundary into another. We compute the ECH capacities of a large family of symplectic four-manifolds with boundary, called "concave toric domains". Examples include the (nondisjoint) union of two ellipsoids in $\mathbb{R}^4$. We use these calculations to find sharp obstructions to certain symplectic embeddings involving concave toric domains. For example: (1) we calculate the Gromov width of every concave toric domain; (2) we show that many inclusions of an ellipsoid into the union of an ellipsoid and a cylinder are "optimal"; and (3) we find a sharp obstruction to ball packings into certain unions of an ellipsoid and a cylinder., 31 pages, 2 figures; fixed one typo, updated references, to appear in Journal of Topology

Recently, the development of computer programs which permit the de novo design of molecular structures satisfying a set of steric and chemical constraints has become a burgeoning area of research and many operational systems have been reported in the literature. Experience with PRO-LIGAND-the de novo design methodology embodied in our in-house molecular design and simulation system PRO-METHEUS-has suggested that the addition of a genetic algorithm (GA) structure refinement procedure can 'add value' to an already useful tool. Starting with the set of designed molecules as an initial population, the GA can combine features from both high- and low-scoring structures and, over a number of generations, produce individuals of better score than any of the starting structures. This paper describes how we have implemented such a procedure and demonstrates its efficacy in improving two sets of molecules generated by different de novo design projects.

In recent years, the importance of considering induced fit effects in molecular docking calculations has been widely recognised in the molecular modelling community. While small-scale protein side-chain movements are now accounted for in many state-of-the-art docking strategies, the explicit modelling of large-scale protein motions such as loop movements in kinase domains is still a challenging task. For this reason ensemble-based methods have been introduced taking into account several discrete protein conformations in the conformational sampling step. Our protein-ligand docking approach GOLD [1,2] has been extended to search such conformational ensembles time-efficiently. The performance of the approach has been assessed on several protein targets using different scoring functions. A detailed analysis of pose prediction and virtual screening results in dependence of the number of protein structures considered in the conformational ensemble will be presented and limitations of the approach will be highlighted.

Src signalling and transduction are directly involved in cell growth, cell cycle, malignant transformation and cell migration, providing therapeutic opportunities through inhibition of Src. Here we report virtual screening for novel compounds that inhibit the Src-SH3 protein–protein interaction with a proline-rich peptide ligand. Computational docking of the ZINC compound database was performed using GOLD. Top-scoring compounds were assayed using a fluorescence polarization-based assay. A benzoquinoline derivative showed micromolar inhibition of binding between Src-SH3 and the proline-rich peptide. Several analogues were subsequently assayed showing the requirement of a linker between the benzoquinoline and phenyl rings, and electron donating substituents on the phenyl ring.

An approach to de novo molecular design, PRO-LIGAND, has been developed that, in the environment of a large, integrated molecular design and simulation system, provides a unified framework for the generation of novel molecules which are either similar or complementary to a specified target. The approach is based on a methodology that has proved to be effective in other studies--placing molecular fragments upon target interaction sites-but incorporates many novel features such as the use of a rapid graph-theoretical algorithm for fragment placing, a generalised driver for structure generation which offers a large variety of fragment assembly strategies to the user and the pre-screening of library fragments. After a detailed description of the relevant modules of the package, PRO-LIGAND's efficacy in aiding rational drug design is demonstrated by its ability to design mimics of methotrexate and potential inhibitors for dihydrofolate reductase and HIV-1 protease.

A computational approach for molecular design, PRO_LIGAND, has been developed within the PROMETHEUS molecular design and simulation system in order to provide a unified framework for the de novo generation of diverse molecules which are either similar or complementary to a specified target. In this instance, the target is a pharmacophore derived from a series of active structures either by a novel interpretation of molecular field analysis data or by a pharmacophore-mapping procedure based on clique detection. After a brief introduction to PRO_LIGAND, a detailed description is given of the two pharmacophore generation procedures and their abilities are demonstrated by the elucidation of pharmacophores for steroid binding and ACE inhibition, respectively. As a further indication of its efficacy in aiding the rational drug design process, PRO_LIGAND is then employed to build novel organic molecules to satisfy the physicochemical constraints implied by the pharmacophores.

Thirty-six compounds, representing six different structural classes of insecticides which are known to act at the gamma-aminobutyric acid receptor/chloride ionophore, have been superimposed by methods which maximise the commonality of steric and electrostatic fields. Maximal steric and electrostatic alignment was derived by pairwise comparisons of the different chemical classes with picrotoxinin. To test the validity of the combined superposition, a Comparative Molecular Field Analysis (CoMFA) was carried out within SYBYL, using recently published in vivo and in vitro binding data for insecticides. The resultant partial least-squares (PLS) analysis of sampled steric and electrostatic fields showed a significant statistical correlation with the published biological data. The predictive model obtained was shown to have a greater than 95% chance of significance.

Kinetic studies are reported for the pseudomolecular rearrangement of N-methylbenzimidates to tertiary amides in nitrobenzene at 138°. The reaction is readily catalysed by alkyl halides (rate =k2[N-methylbenzimidate][alkyl halide]) and is shown to proceed by a two-step mechanism involving a benzimidonium ion intermediate. Formation of this intermediate by an SN2 reaction between substrate and alkyl halide is rate limiting. Quantitative yields of tertiary amide are usually obtained but, for the isopropyl halide catalysed conversion of isopropyl N-methylbenzimidates, a competitive E2 elimination gives ca. 40% propene and N-methylbenzamide. These results are discussed in relation to the ambident nucleophilic properties of neutral amides. They suggest that alkylation occurs more rapidly at the amide oxygen atom to give an imidate (kinetic product) which then rearranges in the presence of alkyl halide to the N-substituted amide (thermodynamic product). It is shown that silver salts inhibit the imidate–amide rearrangement by precipitating nucleophilic anions. This partly explains the preferential O-alkylation of amides in the presence of silver salts.

Within the past fifteen years lipoid pneumonia has been repeatedly reported in the literature. In almost every reported instance the diagnosis was a pathologic one made on autopsy material. In an occasional case the diagnosis was suggested by the history and the clinical findings, and the subsequent improvement followed discontinuance of the use of various oral and nasal oils.1In rare instances oil droplets have been visualized bronchoscopically and the diagnosis made in that way. It occurred to us that biopsy of material aspirated from the lungs, a procedure now in use in the study of obscure pulmonary and mediastinal lesions, would be of value, and we were successful in corroborating the suggested roentgenographic diagnosis of lipoid pneumonia in 5 of 10 cases examined in this way. As far as we can determine, this is the first report of lipoid pneumonia demonstrated by aspiration biopsy. REPORT OF CASES Case