Estimating the synthetic accessibility of molecules with building block and reaction-aware SAScore JCIM. 2024. ISSN: 1758-2946 The one question most chemists ask when viewing molecules generated using computational tools, machine-learning methods or AI models is but how easy is it to make? MedChemica users will know that we use Peter Ertl’s SAScore1 within CoreDesign to

Development of Brain Penetrant Pyridazine Pantothenate Kinase Activators Med. Chem.2024, 67, 14432-14442   Coenzyme A (CoA) is a thiol cofactor that carries carboxylic acid substrates to where they are needed in important metabolic pathways, such as the Citric Acid Cycle. CoA is biosynthesised from pantothenic acid (Vitamin B5). The first and rate-limiting step of this

N‐Substituted Pyrrole-Based Heterocycles as Broad-Spectrum Filoviral Entry Inhibitors   J. Med. Chem.2024, 67, 13737-13764   Emerging pathogenic viruses of pandemic potential remain a global public health concern. In recent decades, outbreaks of 2 significant members of the Filovirus family (Filoviridae): Ebola virus (EBOV) and Marburg virus (MARV) have occurred, resulting in thousands of deaths in

Prediction of Inhibitory Activity against the MATE1 Transporter via Combined Fingerprint- and Physics-Based Machine Learning Models The multidrug and toxin extrusion transporter (MATE1) is located in the renal epithelial cells and mediates efflux of organic cations, like metformin. It is understood that clinical inhibitors of organic cation transporters may also inhibit MATE1, which causes concern

Discovery of JAB-3312, a Potent SHP2 Allosteric Inhibitor for Cancer Treatment Wei Long et al J. Med. Chem. 2024, 67, 13534−13549     This paper in the August addition has promoted a little bit of a SHP2 inhibitor profile – so more a suite of papers than a paper of the month... There are two

Simulation-driven design of stabilized SARS-CoV-2 spike S2 immunogens During the European Federation for Medicinal Chemistry – International Symposium on Medicinal Chemistry (EFMC-ISMC) 2024, I attended an inspiring lecture by Dr Rommie Amaro from University of California in which she enthusiastically demonstrated the usefulness of molecular dynamics simulations to impact drug and vaccine design by increasing

A Second-Generation Oral SARS-CoV‑2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19   At the start of the decade, amidst the SARS-CoV-2 pandemic, there was a huge amount of interest in the rapid development and delivery of antiviral therapeutics to those in need. Among others,[ doi.org/10.1126/science.abo7201] Pfizer rose to this challenge with a

Deriving general structure–activity/selectivity relationship patterns for different subfamilies of cyclin-dependent kinase inhibitors using machine learning methods Kaveh, S. et al. Deriving general structure–activity/selectivity relationship patterns for different subfamilies of cyclin-dependent kinase inhibitors using machine learning methods. Sci. Rep.14, 15315 (2024). doi.org/10.1038/s41598-024-66173-z The importance of explainable AI in guiding medicinal chemistry design is becoming increasingly evident.

One Chiral Fingerprint To Find Them All Markus Orsi & Jean-Louis Reymond. J. Cheminform., 2024, 16:53 doi: 10.1186/s13321-024-00849-6 In Chemoinformatics there are a few problems that always rear their ugly heads and stereochemistry is one of them, even though many computational tools use fingerprints which generally do not consider this. Orsi and Reymond have created

Identification of Novel, Selective Ataxia-Telangiectasia Mutated Kinase Inhibitors with the Ability to Penetrate the Blood−Brain Barrier: The Discovery of AZD1390 Achieving CNS penetration, when desired, is a hugely important and sometimes very difficult hurdle to overcome. To do this, the Blood-Brain Barrier (BBB): with its unique lining of endothelial cells and its cocktail of efflux