Discovery of a series of 2-(pyridinyl) pyrimidines as potent antagonists of GPR40

A series of 2-(pyridinyl)pyrimidines were identified as potent GPR40 antagonists. Despite significant challenges related to improving the combination of potency and lipophilicity within the series, the compounds were optimised to identify a suitable in vivo probe compound, which was confirmed to exhibit pharmacology consistent with GPR40 antagonism

Can we accelerate medicinal chemistry by augmenting the chemist with Big Data and artificial intelligence?

It is both the best of times and the worst of times to be a medicinal chemist. Massive amounts of data combined with machine-learning and/or artificial intelligence (AI) tools to analyze it can increase our capabilities. However, drug discovery faces severe economic pressure and a high level of societal need set against challenging targets. Here, we show how improving medicinal chemistry by better curating and exchanging knowledge can contribute to improving drug hunting in all disease areas. Although securing intellectual property (IP) is a critical task for medicinal chemists, it impedes the sharing of generic medicinal chemistry knowledge. Recent developments enable the sharing of knowledge both within and between organizations while securing IP. We also explore the effects of the structure of the corporate ecosystem within drug discovery on knowledge sharing

An Orally Bioavailable, Indole-3-glyoxylamide Based Series of Tubulin Polymerization Inhibitors Showing Tumor Growth Inhibition in a Mouse Xenograft Model of Head and Neck Cancer.

A number of indole-3-glyoxylamides have previously been reported as tubulin polymerization inhibitors, although none has yet been successfully developed clinically. We report here a new series of related compounds, modified according to a strategy of reducing aromatic ring count and introducing a greater degree of saturation, which retain potent tubulin polymerization activity but with a distinct SAR from previously documented libraries. A subset of active compounds from the reported series is shown to interact with tubulin at the colchicine binding site, disrupt the cellular microtubule network, and exert a cytotoxic effect against multiple cancer cell lines. Two compounds demonstrated significant tumor growth inhibition in a mouse xenograft model of head and neck cancer, a type of the disease which often proves resistant to chemotherapy, supporting further development of the current series as potential new therapeutics

AI3SD Video: What a Medicinal Chemist Needs to Know about Explainable Artificial Intelligence

The latest developments in artificial intelligence (AI) have arrived into an existing state of creative tension between computational and medicinal chemists.  At their most productive, medicinal and computational chemists have made significant progress in delivering new therapeutic agents into the clinic.  However, the relationship between these communities has the prospect of being weakened by application of over-simplistic AI methods which, if they fail to deliver, will reinforce unproductive prejudices.  AI systems are action orientated; they suggest, and even automate, possible steps to take next in drug hunting projects. They do this by generating options, preforming predictions, then ranking the options. A key piece of critical learning is that any AI system for chemists should be open and ‘explainable’. The requirement for the chemist to understand how models have been built and ‘drill back’ to original data is key to explain how the computer has arrived at the prediction. For example, an AI system that aids the medicinal chemist in evaluating and designing new biologically active compounds should focus on communicating, in the preferred mode of the medicinal chemist, via critical substructures, and map to the original compounds and test data on which the model was built. Without this, any model becomes labelled as ‘black-box’ and confidence is reduced in the suggestions made. Therefore, to develop them further and to understand the quality of any prediction, transparency and auditability should be designed into a system from inception (see example below where the predictions are made for a compound and the contributions from the model highlighted). The talk will show practical examples from drug discovery projects and recent compounds from the global Covid Moonshot drug discovery program

Humans of AI3SD: Dr Al Dossetter

This forms part of our Humans of AI3SD Series.In this Humans of AI4SD interview he discusses whether the rules of medicinal chemistry actually work, achieving `sensible AI', and the importance of being able to learn quickly

Tunnelman luominen tanssiteoksen ilmeeseen

Opinnäytetyön teemana ovat lapsuuden painajaiset. Kyseessä on taiteellinen produk-tio, joka tarkastelee painajaisten, katoamisen ja näkymisen teemaa liikekielen, kuvan ja typografian keinoin. Usean kuukauden kestänyt projekti edellytti syvää paneutumista aiheeseen. Työ on saanut vaikutteita musiikin, kirjallisuuden ja elokuvateollisuuden kauhugenrestä. Opinnäytetyön tutkielma käsittelee tunnelman luomista tanssiteoksen ilmeessä. Kirjal-linen osio jakautuu kahteen päälukuun: tanssiteoksen visuaaliseen ilmeeseen ja esityk-seen. Graafiseen ilmeeseen lukeutuvat juliste, käsiohjelma, kutsukortti, notaatio ja In-ternet-sivut. Tanssiteoksen suunnitteluun kuuluvat koreografia, lavastus, puvustus ja äänisuunnittelu. Teoksen tekniseen toteutukseen on saatu apua Kymenlaakson ammat-tikorkeakoulun audiovisuaalisen ilmaisun opiskelijoilta. Työn tarkoituksena oli päästä eroon pimeän peloista ja öisin mielikuviin ilmestyvistä mustista hahmoista. Tutkimukseen on kerätty materiaalia lukemalla kirjallisuutta, haastattelemalla ihmisiä, tutustumalla kauhugenreen ja syventymällä omiin painajaiskokemuksiin. Inspiraation lähteinä ovat erityisesti olleet lähiympäristössä tapahtuneet yliluonnolliset ilmiöt ja kauhutarinat. Lopputuloksena tunnelma ei korostunut ainoastaan konkreettisesti vaan myös aineet-tomasti. Prosessin seurauksena tanssiteokseen syntyi sekä fyysinen tila, jossa kauhu nähtiin, että henkinen tila, jossa kauhu aistittiin. Unien pelkotilat ja pimeässä muodos-tuneet hahmot alkoivat vähitellen kadota, kun turtuminen kauhumaailmaan sai otteen.To begin with, the thesis was inspired by fear. In other words, the theme of the thesis was based on childhood nightmares and traumatic memories. All the words, sentences and images have arisen after two months of paranormal research. The thesis was divided into two parts: the visual identity of the contemporary dance show and the dance performance. A poster, a brochure, an invitation card, a notation and an Internet website were included in the visual identity. Theatrical elements, such as choreography, staging, costumes and sound design were included in the dance per-formance. However, the thesis focuses on describing the atmosphere in the visualiza-tion of the dance performance. The main goal of the process was to release the sensi-tive mind and to get rid of the fear of darkness and imaginary creatures. The material for the thesis was collected by reading literature, interviewing people, experiencing dreams and getting absorbed in the horror genre. The performance was inspired by ghost stories and supernatural phenomena in a real life. The atmosphere highlighted not only in a physical but also in a mental way. Eventu-ally, instead of only one stage, two scenes arose as a result of the process. The first one was regarded as a physical scene where horror was seen. The second one was considered a mental scene where the images of nightmare stemmed from. The fear of darkness alleviated due to the examination of the theme and becoming numb for the genre. Little by little, imaginary creatures came to be regarded as insignificant