Tools,techniques, organisation and culture of the CADD group at Sygnature Discovery

Computer-aided drug design encompasses a wide variety of tools and techniques, and can be implemented with a range of organisational structures and focus in different organisations. Here we outline the computational chemistry skills within Sygnature Discovery, along with the software and hardware at our disposal, and briefly discuss the methods that are not employed and why. The goal of the group is to provide support for design and analysis in order to improve the quality of compounds synthesised and reduce the timelines of drug discovery projects, and we reveal how this is achieved at Sygnature. Impact on medicinal chemistry is vital to demonstrating the value of computational chemistry, and we discuss the approaches taken to influence the list of compounds for synthesis, and how we recognise success. Finally we touch on some of the areas being developed within the team in order to provide further value to the projects and clients.     

Intrinsic dosimetry of glass containers: a potential interrogation tool for nuclear forensics and waste management

Intrinsic dosimetry is the method of measuring total absorbed dose received by the walls of a container holding radioactive material. By considering the total absorbed dose received by a container in tandem with the physical characteristics of the radioactive material housed within that container, this method has the potential to provide enhanced pathway information regarding the history of the container and its radioactive contents. We report the latest in a series of experiments designed to validate and demonstrate this newly developed tool. Thermoluminescence (TL) dosimetry was used to measure dose effects on raw stock borosilicate container glass up to 70 days after gamma ray, X-ray, beta particle or ultraviolet irradiations at doses from 0.15 to 20 Gy. Two main peaks were identified in the TL glow curve when irradiated with ⁶⁰Co, a relatively unstable peak around 120 °C and a more stable peak around 225 °C. Signal strength of both peaks decayed with time. The minimum measurable dose using this technique is 0.15 Gy, which is roughly equivalent to a 24 h irradiation at 1 cm from a 50 ng ⁶⁰Co source. As a result of fading, this dose would be detectable for approximately 1 year post-irradiation. In a more detailed analysis, the TL glow curves were separated into five peaks centered near 120, 160, 225, 300, and 340 °C. Differences in TL glow curve shape and intensity were observed for the glasses from different geographical origins. These differences can be explained by changes in the intensities of the five peaks. This suggests that mechanisms controlling radiation induced defect formation from gamma, beta, X-ray, and UV sources may be similar.     

Nonuniqueness of Weak Solutions to the SQG Equation

We prove that weak solutions of the inviscid SQG equations are not unique, thereby answering Open Problem 11 of De Lellis and Székelyhidi in 2012. Moreover, we also show that weak solutions of the dissipative SQG equation are not unique, even if the fractional dissipation is stronger than the square root of the Laplacian. In view of the results of Marchand in 2008, we establish that for the dissipative SQG equation, weak solutions may be constructed in the same function space both via classical weak compactness arguments and via convex integration. © 2019 Wiley Periodicals, Inc.     

A new noncovalent force: comparison of P···N interaction with hydrogen and halogen bonds

When PH(3) is paired with NH(3), the two molecules are oriented such that the P and N atoms face one another directly, without the intermediacy of a H atom. Quantum calculations indicate that this attraction is due in part to the transfer of electron density from the lone pair of the N atom to the σ(?) antibond of a P-H covalent bond. Unlike a H-bond, the pertinent hydrogen is oriented about 180° away from, instead of toward, the N, and the N lone pair overlaps with the lobe of the P-H σ(?) orbital that is closest to the P. In contrast to halogen bonds, there is no requirement of a σ-hole of positive electrostatic potential on the P atom, nor is it necessary for the two interacting atoms to be of differing potential. In fact, the two atoms can be identical, as the global minimum of the PH(3) homodimer has the same structure, characterized by a P···P attraction. Natural bond orbital analysis, energy decomposition, and visualization of total electron density shifts reveal other similarities and differences between the three sorts of molecular interaction.     

Insights into the effects of functional groups on carbon nanotubes for the electrooxidation of methanol

Functionalized carbon nanotubes were used as a support for PtCo nanoparticles. Their performance as electrocatalysts for the electrooxidation of methanol was evaluated by cyclic voltammetry and in situ FTIR reflectance spectroscopy. The onset potentials for both the electrooxidation of methanol and the production of CO(2) shifted to less positive values for catalysts prepared with more oxygen groups on the support. Furthermore, the production of CO(2) was higher on catalysts prepared with functionalized carbon nanotubes. The functional groups play two different but complementary roles. On the one hand, they help to stabilize smaller PtCo particles of ca. 3 nm. On the other hand, they provide the -OH groups necessary for the total oxidation of methanol to CO(2) at potentials less positive than on nonfunctionalized supports. Remarkably, the consumption of carboxylic acid groups along with the production of water is observed in the infrared spectra of the functionalized supports recorded during the electrooxidation of methanol. This observation suggests that the -OH groups of the support can also react with methanol, forming water and an ester.     

Effects of substituents upon the P···N noncovalent interaction: the limits of its strength

Previous work has documented the ability of the P atom to form a direct attractive noncovalent interaction with a N atom, based in large measure on the charge transfer from the N lone pair into the σ* antibonding orbital of the P-H that is turned away from the N atom. As the systems studied to date include only hydrides, the present work considers how substituents affect the interaction and examines whether P···N might compete with other attractive forces such as H-bonds. It is found that the addition of electron-withdrawing substituents greatly strengthens the P···N interaction to the point where it exceeds that of the majority of H-bonds. The highest interaction energy occurs in the FH(2)P···N(CH(3))(3) complex, amounting to 11 kcal/mol. A breakdown of the individual forces involved attributes the stability of the interaction to approximately equal parts electrostatic and induction energy, with a smaller contribution from dispersion.     

Artifacts Induced by Selective Blanking of Time-Domain Data in Fourier Transform Mass Spectrometry

Fourier transform mass spectrometry (FTMS) of the isolated isotopic distribution for a highly charged biomolecule produces time-domain signal containing large amplitude signal “beats” separated by extended periods of much lower signal magnitude. Signal-to-noise ratio for data sampled between beats is low because of destructive interference of the signals induced by members of the isotopic distribution. Selective blanking of the data between beats has been used to increase spectral signal-to-noise ratio. However, blanking also eliminates signal components and, thus, can potentially distort the resulting FT spectrum. Here, we simulate the time-domain signal from a truncated isotopic distribution for a single charge state of an antibody. Comparison of the FT spectra produced with or without blanking and with or without added noise clearly show that blanking does not improve mass accuracy and introduces spurious peaks at both ends of the isotopic distribution (thereby making it more difficult to identify posttranslational modifications and/or adducts). Although the artifacts are reduced by use of multiple Gaussian (rather than square wave) windowing, blanking appears to offer no advantages for identifying true peaks or for mass measurement.

Robust portfolio optimization with derivative insurance guarantees

Robust portfolio optimization aims to maximize the worst-case portfolio return given that the asset returns are allowed to vary within a prescribed uncertainty set. If the uncertainty set is not too large, the resulting portfolio performs well under normal market conditions. However, its performance may substantially degrade in the presence of market crashes, that is, if the asset returns materialize far outside of the uncertainty set. We propose a novel robust optimization model for designing portfolios that include European-style options. This model trades off weak and strong guarantees on the worst-case portfolio return. The weak guarantee applies as long as the asset returns are realized within the prescribed uncertainty set, while the strong guarantee applies for all possible asset returns. The resulting model constitutes a convex second-order cone program, which is amenable to efficient numerical solution procedures. We evaluate the model using simulated and empirical backtests and analyze the impact of the insurance guarantees on the portfolio performance.     

Classification of regular embeddings of <Emphasis Type="Italic">n</Emphasis>-dimensional cubes

An orientably-regular map is a 2-cell embedding of a connected graph or multigraph into an orientable surface, such that the group of all orientation-preserving automorphisms of the embedding has a single orbit on the set of all arcs (incident vertex-edge pairs). Such embeddings of the n-dimensional cubes Q _n were classified for all odd n by Du, Kwak and Nedela in 2005, and in 2007, Jing Xu proved that for n=2m where m is odd, they are precisely the embeddings constructed by Kwon in 2004. Here, we give a classification of orientably-regular embeddings of Q _n for all n. In particular, we show that for all even n (=2m), these embeddings are in one-to-one correspondence with elements σ of order 1 or 2 in the symmetric group S _n such that σ fixes n, preserves the set of all pairs B _i ={i,i+m} for 1≤i≤m, and induces the same permutation on this set as the permutation B _i ↦ B _f(i) for some additive bijection f:ℤ _m →ℤ _m . We also give formulae for the numbers of embeddings that are reflexible and chiral, respectively, showing that the ratio of reflexible to chiral embeddings tends to zero for large even n.