Performance estimation of interior permanent-magnet brushless motors using the voltage-driven flux-MMF diagram

The flux-magnetomotive force (flux-MMF) diagram, or "energy conversion loop," is a powerful tool for computing the parameters of saturated interior permanent-magnet brushless motors, especially when the assumptions underlying classical dq theory are not valid, as is often the case in modern practice. Efficient finite-element computation of the flux-MMF diagram is possible when the motor current is known a priori, but in high-speed operation the current regulator can lose control of the current waveform and the computation becomes "voltage-driven" rather than "current-driven." This paper describes an efficient method for estimating the motor performance-average torque, inductances-by solving the voltage-driven problem. It presents experimental validation for a two-pole brushless interior permanent-magnet motor. The paper also discusses the general conditions under which this method is appropriate, and compares the method with alternative approaches

Simulation and Analysis of Magnetisation Characteristics of Interior Permanent Magnet Motors

Modern permanent magnet (PM) synchronous brushless machines often have magnetic circuits in which the patterns of saturation are complex and highly variable with the position of the rotor. The classical phasor diagram theory of operation relies on the assumption of sinusoidal variation of flux-linkage with rotor position, and neglects the non-linear effects that arise in different operating states. The finite element method is a useful tool for detailed magnetic analysis, but it is important to verify simulation results by direct measurement of the magnetic characteristics of the motor, in terms of “magnetisation curves” of current and flux-linkage. This paper presents results from finite element simulations to determine the magnetisation in a split-phase interior permanent magnet (IPM) motor. Investigation has been made to determine the effects of the rotor geometry on the synchronous reactances and airgap flux distribution. Comparisons are made with a second IPM motor with a different rotor configuration.

Embedded finite-element solver for computation of brushless permanent-magnet motors

This paper describes the theory underlying the formulation of a “minimum set” of finite-element solutions to be used in the design and analysis of saturated brushless permanent-magnet motors. The choice of finite-element solutions is described in terms of key points on the flux–MMF diagram. When the diagram has a regular shape, a huge reduction in finite-element analysis is possible with no loss of accuracy. If the loop is irregular, many more solutions are needed. This paper describes an efficient technique in which a finite-element solver is associated with a classical $d$– $q$-axis circuit model in such a way that the number of finite-element solutions in one electrical half-cycle can be varied between 1 and 360. The finite-element process is used to determine not only the average torque but also the saturated inductances as the rotor rotates

Recent Developments in the Use of Flow Hydrogenation in the Field of Medicinal Chemistry

This chapter focuses on recent applications of flow hydrogenation in medicinal chemistry. Flow reactors can enhance laboratory safety, reducing the risks associated with pyrophoric catalysts, due to their containment in catalyst cartridges or omnifit columns. Flow hydrogenation reduces the risks arising from hydrogen gas, with either hydrogen generated in situ from water, or precise management of the gas flow rate through tube-in-tube reactors. There is an increasing body of evidence that flow hydrogenation enhances reduction outcomes across nitro, imine, nitrile, amide, azide, and azo reductions, together with de-aromatisation and hydrodehalogenation. In addition, olefin, alkyne, carbonyl, and benzyl reductions have been widely examined. Further, protocols involving multistage flow reactions involving hydrogenation are highlighted

Discovery of 14-3-3 PPI Stabilizers by Extension of an Amidine-Substituted Thiophene Fragment

Protein-protein interaction (PPI) modulation is a promising approach in drug discovery with the potential to expand the 'druggable' proteome and develop new therapeutic strategies. While there have been significant advancements in methodologies for developing PPI inhibitors, there is a relative scarcity of literature describing the 'bottom-up' development of PPI stabilizers (Molecular Glues). The hub protein 14-3-3 and its interactome provide an excellent platform for exploring conceptual approaches to PPI modulation, including evolution of chemical matter for Molecular Glues. In this study, we employed a fragment extension strategy to discover stabilizers for the complex of 14-3-3 protein and an Estrogen Receptor alpha-derived peptide (ERα). A focused library of analogues derived from an amidine-substituted thiophene fragment enhanced the affinity of the 14-3-3/ERα complex up to 6.2-fold. Structure-activity relationship (SAR) analysis underscored the importance of the newly added, aromatic side chain with a certain degree of rigidity. X-ray structural analysis revealed a unique intermolecular π-π stacking binding mode of the most active analogues, resulting in the simultaneous binding of two molecules to the PPI binding pocket. Notably, analogue 11 displayed selective stabilization of the 14-3-3/ERα complex.</p

Mapping the cortical representation of the lumbar paravertebral muscles

Objective: The aim of this study was to map the cortical representation of the lumbar spine paravertebral (LP) muscles in healthy subjects. Methods: Transcranial magnetic stimulation (TMS) was employed to map the cortical representations of the LP muscles at two sites. Stimuli were applied to points on a grid representing scalp positions. The amplitude of motor evoked potentials (n = 6) was averaged for each position. Results: The optimal site for evoking responses in the contralateral LP muscles was situated 1 cm anterior and 4 cm lateral to the vertex. Ipsilateral responses were evoked from sites lateral to the optimal site for evoking contralateral responses. Contralateral responses were also obtained from areas anterior to the optimal site. Conclusions: Maps of these muscles can be produced. The results suggest discrete contra- and ipsilateral cortical projections. Anterior sites at which excitation can be evoked may indicate projections arising in the SMA are involved. Significance: This study provides normative data regarding the cortical representation of the paravertebral muscles and provides a technique for evaluating cortical motor plasticity in patients presenting with spinal pathologies

Reversible Dual-Covalent Molecular Locking of the 14-3-3/ERRγ Protein-Protein Interaction as a Molecular Glue Drug Discovery Approach

Molecules that stabilize protein-protein interactions (PPIs) are invaluable as tool compounds for biophysics and (structural) biology, and as starting points for molecular glue drug discovery. However, identifying initial starting points for PPI stabilizing matter is highly challenging, and chemical optimization is labor-intensive. Inspired by chemical crosslinking and reversible covalent fragment-based drug discovery, we developed an approach that we term “molecular locks” to rapidly access molecular glue-like tool compounds. These dual-covalent small molecules reversibly react with a nucleophilic amino acid on each of the partner proteins to dynamically crosslink the protein complex. The PPI between the hub protein 14-3-3 and estrogen-related receptor γ (ERRγ) was used as a pharmacologically relevant case study. Based on a focused library of dual-reactive small molecules, a molecular glue tool compound was rapidly developed. Biochemical assays and X-ray crystallographic studies validated the ternary covalent complex formation and overall PPI stabilization via dynamic covalent crosslinking. The molecular lock approach is highly selective for the specific 14-3-3/ERRγ complex, over other 14-3-3 complexes. This selectivity is driven by the interplay of molecular reactivity and molecular recognition of the composite PPI binding interface. The long lifetime of the dual-covalent locks enabled the selective stabilization of the 14-3-3/ERRγ complex even in the presence of several other competing 14-3-3 clients with higher intrinsic binding affinities. The molecular lock approach enables systematic, selective, and potent stabilization of protein complexes to support molecular glue drug discovery.</p

Molecular basis and dual ligand regulation of tetrameric Estrogen Receptor α/14-3-3ζ protein complex

Therapeutic strategies targeting Nuclear Receptors (NRs) beyond their endogenous ligand binding pocket have gained significant scientific interest, driven by a need to circumvent problems associated with drug resistance and pharmacological profile. The hub protein 14-3-3 is an endogenous regulator of various NRs, providing a novel entry point for small molecule modulation of NR activity. Exemplified, 14-3-3 binding to the C-terminal F-domain of the Estrogen Receptor alpha (ERα), and small molecule stabilization of the ERα/14-3-3ζ protein complex by the natural product Fusicoccin A (FC-A), was demonstrated to downregulate ERα-mediated breast cancer proliferation. This presents a novel drug discovery approach to target ERα, however, structural and mechanistic insights into ERα/14-3-3 complex formation are lacking. Here, we provide an in-depth molecular understanding of the ERα/14-3-3ζ complex by isolating 14-3-3ζ in complex with an ERα protein construct comprising its Ligand Binding Domain (LBD) and phosphorylated F-domain. Bacterial co-expression and co-purification of the ERα/14-3-3ζ complex, followed by extensive biophysical and structural characterization, revealed a tetrameric complex between the ERα homodimer and the 14-3-3ζ homodimer. 14-3-3ζ binding to ERα, and ERα/14-3-3ζ complex stabilization by FC-A, appeared to be orthogonal to ERα endogenous agonist (E2) binding, E2-induced conformational changes, and cofactor recruitment. Similarly, the ERα antagonist 4-hydroxytamoxifen inhibited cofactor recruitment to the ERα LBD while ERα was bound to 14-3-3ζ. Furthermore, stabilization of the ERα/14-3-3ζ protein complex by FC-A was not influenced by the disease-associated and 4-hydroxytamoxifen resistant ERα-Y537S mutant. Together, these molecular and mechanistic insights provide direction for targeting ERα via the ERα/14-3-3 complex as an alternative drug discovery approach.</p

A simple method for developing lysine targeted covalent protein reagents

Peptide-based covalent probes can target shallow protein surfaces not typically addressable using small molecules, yet there is a need for versatile approaches to convert native peptide sequences into covalent binders that can target a broad range of residues. Here we report protein-based thio-methacrylate esters—electrophiles that can be installed easily on unprotected peptides and proteins via cysteine side chains, and react efficiently and selectively with cysteine and lysine side chains on the target. Methacrylate phosphopeptides derived from 14-3-3-binding proteins irreversibly label 14-3-3σ via either lysine or cysteine residues, depending on the position of the electrophile. Methacrylate peptides targeting a conserved lysine residue exhibit pan-isoform binding of 14-3-3 proteins both in lysates and in extracellular media. Finally, we apply this approach to develop protein-based covalent binders. A methacrylate-modified variant of the colicin E9 immunity protein irreversibly binds to the E9 DNAse, resulting in significantly higher thermal stability relative to the non-covalent complex. Our approach offers a simple and versatile route to convert peptides and proteins into potent covalent binders.</p