Fragment-to-Lead Medicinal Chemistry Publications in 2018

This Perspective, the fourth in an annual series, summarizes fragment-to-lead (F2L) success stories published during 2018. Topics such as target class, screening methods, physicochemical properties, and ligand efficiency are discussed for the 2018 examples as well as for the combined 111 F2L examples covering 2015-2018. While the overall properties of fragments and leads have remained constant, a number of new trends are noted, for example, broadening of target class coverage and application of FBDD to covalent inhibitors. Moreover, several studies make use of fragment hits that were previously described in the literature, illustrating that fragments are versatile starting points that can be optimized to structurally diverse leads. By focusing on success stories, the hope is that this Perspective will identify and inform best practices in fragment-based drug discovery.</p

Preventing infective complications following leech therapy: Is practice keeping pace with current research?

Background: Despite several publications strongly advocating prophylactic antibiotics during leech therapy, and recent primary articles shedding new light on the microbiota of leeches, many units either do not use antibiotic prophylaxis, or are continuing to use ineffective agents. Methods: A 5-year follow-up of plastic surgery units in the United Kingdom and the Republic of Ireland was conducted in 2007 to ascertain current practice regarding the use of prophylactic antibiotics with leech therapy. A comprehensive literature search investigated primary research articles regarding the microbiota of leeches to update the reconstructive surgery community. Results: Despite published evidence to support the use of prophylactic antibiotics during leech therapy, 24% of units do not use antibiotic prophylaxis and 57% of those using antibiotics are using potentially ineffective agents. Advanced molecular genetic techniques, which allow accurate characterization of both culturable and nonculturable microbiota of the leech digestive tract, show a wider diversity than at first thought, with variable antiobiotic resistance profiles. Conclusions: Despite infection due to leech therapy being a well known and relatively common complication, many units are not using appropriate antibiotic prophylaxis. © 2009 Wiley-Liss, Inc. Microsurgery 2009

CAD modeling, multibody system formalisms and visualization : an integrated approach

In this paper an integrated approach of CAD (Computer Aided Design) modeling, generation of equations of motion, simulation and visualization of multibody systems is described. An object-oriented data model for different multibody formalisms is integrated in a commercially available CAD-3D-system. With respect to existing CAD-interfaces, different solid model design methods and various visualization demands the datamodel allow, multi body modeling with a direct interface to a data base. Different software tools like an integrated Newton-Euler formalism are able to use immediately the parametrized multi body system data base. For multibody systems with closed kinematic loops a set of ordinary differential equations and decoupled algebraic equations is formulated automatically which can be solved with explicit multistep integration algorithms. This is achieved by a minimal set of generalized coordinates being specified during the numerical integration. A additional interface provides data for visualization from the simulation tool

Exile

Byron rehearsed going into exile in 1809, when he was twenty-one years old. Before setting sail for Lisbon, he wrote, “I leave England without regret, I shall return to it without pleasure. – I am like Adam the first convict sentenced to transportation, but I have no Eve, and have eaten no apple but what was sour as a crab and thus ends my first Chapter” (BLJ 1: 211). Byron’s sardonic perception of himself as a biblical exile foreshadowed the allusive character of his second longer-term exile at the age of twenty-eight, when his carefully staged exit required an audience (some of the same friends and servants), expensive props (a replica of Napoleon’s carriage) and a literary precursor. On his last evening in England, Byron visited the burial place of the satirist Charles Churchill, and lay down on his grave. It was a performance of immense weariness with life and solidarity with an embittered outcast.Postprin

The Lake Poets

“If Southey had not been comparatively good,” writes Herbert F. Tucker, “he would never have drawn out Byron’s best in those satirical volleys that were undertaken, at bottom, in order to reprehend not the want of talent but its wastage.” And if Wordsworth and Coleridge had not been dangerously talented, Byron might have spared them some of his stinging sallies. In Table Talk Coleridge proclaimed the conclusion of the “intellectual war” Byron threatened in Don Juan (XI. 62: 496), declaring Wordsworth the poet who “will wear the crown,” triumphing over Byron and his ilk for the poetic laurels of the Romantic period. But Byron was not simply an opponent of his contemporaries. His responses to the Lake poets, particularly to Wordsworth, ran the gamut from “reverence” (HVSV, 129) then “nausea” (Medwin, 237) to Don Juan’s comical though cutting disdain, in under a decade. Focusing on Byron’s relationship with Wordsworth and Coleridge, I will show how Byron’s poetry and drama reveal the range and complexity of his dialogue with his older peers, where, even at their most apparently divergent, the conversation between the poets reveals the depth of the engagement across their works

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology