Applying medicinal chemistry transformations and multiparameter optimization to guide the search for high-quality leads and candidates

In this article we describe a computational method that automatically generates chemically relevant compound ideas from an initial molecule, closely integrated with in silico models, and a probabilistic scoring algorithm to highlight the compound ideas most likely to satisfy a user-defined profile of required properties. The new compound ideas are generated using medicinal chemistry 'transformation rules' taken from examples in the literature. We demonstrate that the set of 206 transformations employed is generally applicable, produces a wide range of new compounds, and is representative of the types of modifications previously made to move from lead-like to drug-like compounds. Furthermore, we show that more than 94% of the compounds generated by transformation of typical drug-like molecules are acceptable to experienced medicinal chemists. Finally, we illustrate an application of our approach to the lead that ultimately led to the discovery of duloxetine, a marketed serotonin reuptake inhibitor.     

Palladium catalyzed alkoxy- and aminocarbonylation of vinyl tosylates

The palladium catalyzed alkoxycarbonylation and aminocarbonylation of vinyl tosylates are described. A variety of ketone and aldehyde derived vinyl tosylates may be carbonylated in the presence of primary, secondary, and tertiary alcohols, or primary and secondary amines, to provide the corresponding esters and amides in good yields. The alkoxycarbonylation was applied to a short synthesis of isoguvacine.     

Bio-electrosprayed living composite matrix implanted into mouse models

We show that composite de novo structures can be generated using bio-electrosprays. Mouse lung fibroblasts are bio-electrosprayed directly with a biopolymer to form cell-bearing matrices, which are viable even when implanted subcutaneously into murine hosts. Generated cell-bearing matrices are assessed in-vitro and found to undergo all expected cellular behaviour. Subsequent in-vivo studies demonstrate the implanted living matrices integrating as expected with the surrounding microenvironment. The in-vitro and in-vivo studies elucidate and validate the ability for either bio-electrosprays or cell electrospinning to form a desired living architecture for undergoing investigation for repairing, replacing and rejuvenating damaged and/or ageing tissues.     

The effect of cyclone inlet dimensions on the flow pattern and performance

The effect of the cyclone inlet dimensions on the performance and flow field pattern has been investigated computationally using the Reynolds stress turbulence model (RSM) for five cyclone separators. The results show that, the maximum tangential velocity in the cyclone decreases with increasing the cyclone inlet dimensions. No acceleration occurs in the cyclone space (the maximum tangential velocity is nearly constant throughout the cyclone). Increasing the cyclone inlet dimensions decreases the pressure drop. The cyclone cut-off diameter increases with increasing cyclone inlet dimension (consequently, the cyclone overall efficiency decreases due to weakness of the vortex strength). The effect of changing the inlet width is more significant than the inlet height especially for the cut-off diameter. The optimum ratio of inlet width to inlet height b/a is from 0.5 to 0.7.     

The cross-entropy method in multi-objective optimisation: An assessment

Solving multi-objective problems requires the evaluation of two or more conflicting objective functions, which often demands a high amount of computational power. This demand increases rapidly when estimating values for objective functions of dynamic, stochastic problems, since a number of observations are needed for each evaluation set, of which there could be many. Computer simulation applications of real-world optimisations often suffer due to this phenomenon. Evolutionary algorithms are often applied to multi-objective problems. In this article, the cross-entropy method is proposed as an alternative, since it has been proven to converge quickly in the case of single-objective optimisation problems. We adapted the basic cross-entropy method for multi-objective optimisation and applied the proposed algorithm to known test problems. This was followed by an application to a dynamic, stochastic problem where a computer simulation model provides the objective function set. The results show that acceptable results can be obtained while doing relatively few evaluations.     

Singular monopoles from Cheshire bows

Singular monopoles are nonabelian monopoles with prescribed Dirac-type singularities. All of them are delivered by Nahm's construction. In practice, however, the effectiveness of the latter is limited to the cases of one or two singularities. We present an alternative construction of singular monopoles formulated in terms of Cheshire bows. To illustrate the advantages of our bow construction we obtain an explicit expression for one U(2)$U(2)$ gauge group monopole with any given number of singularities of Dirac type.     

Ladder-type P,S-bridged trans-stilbenes

Phosphole-containing π-systems have emerged as building blocks with enormous potential as electronic materials because of the tunability of the phosphorus center. Among these, asymmetric P-bridged trans-stilbenes are still rare, and here an elegant and efficient synthesis toward such fluorescent molecular frameworks is described. Fine-tuning of the photophysical properties is attempted by enforcing the planarization of the phosphorus tripod and thus increasing the interaction between the phosphorus lone pair and the π-system. The electronic structure of the π-conjugated frameworks is analyzed with NMR, UV-vis and fluorescence spectroscopy, and time-dependent density functional theory (TD-DFT) calculations.     

Electrostatic embedding in large-scale first principles quantum mechanical calculations on biomolecules

Biomolecular simulations with atomistic detail are often required to describe interactions with chemical accuracy for applications such as the calculation of free energies of binding or chemical reactions in enzymes. Force fields are typically used for this task but these rely on extensive parameterisation which in cases can lead to limited accuracy and transferability, for example for ligands with unusual functional groups. These limitations can be overcome with first principles calculations with methods such as density functional theory (DFT) but at a much higher computational cost. The use of electrostatic embedding can significantly reduce this cost by representing a portion of the simulated system in terms of highly localised charge distributions. These classical charge distributions are electrostatically coupled with the quantum system and represent the effect of the environment in which the quantum system is embedded. In this paper we describe and evaluate such an embedding scheme in which the polarisation of the electronic density by the embedding charges occurs self-consistently during the calculation of the density. We have implemented this scheme in a linear-scaling DFT program as our aim is to treat with DFT entire biomolecules (such as proteins) and large portions of the solvent. We test this approach in the calculation of interaction energies of ligands with biomolecules and solvent and investigate under what conditions these can be obtained with the same level of accuracy as when the entire system is described by DFT, for a variety of neutral and charged species.     

High-resolution Fourier-transform infrared spectroscopy of the Coriolis coupled ground state and ν7 mode of ketenimine

High resolution FTIR spectra of the short lived species ketenimine have been recorded in the regions 390-1300 cm(-1) and 20-110 cm(-1) using synchrotron radiation. Two thousand six hundred sixty transitions of the ν(7) band centered at 693 cm(-1) and 126 far-IR rotational transitions have been assigned. Rotational and centrifugal distortion parameters for the ν(7) mode were determined and local Fermi and b-axis Coriolis interactions with 2ν(12) are treated. A further refinement of the ground state, ν(12) and ν(8) parameters was also achieved, including the treatment of previously unrecognized ac-axis and ab-axis second order perturbations to the ground state.