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
The First ATP Competitive Type-III c-MET Inhibitor? In this paper, the target was c-MET, which is a receptor tyrosine kinase implicated in the development of tumour cells. Hyperactivation of c-MET is associated with poor prognoses in cancer patients, including tumour survival and metastasis. Existing inhibitors of c-MET are clustered into types, depending on their site
Where Old Meets New: Advancements in AlphaFold with Some Help From Boltzmann With the news saturated by the opportunities presented by AI, it’s easy to assume that AI alone holds all of the answers to our problems in computer-aided drug discovery. Indeed, the release of the ground-breaking protein structure prediction tool AlphaFold2, was an
Fast calculation of hydrogen-bond strengths and free energy of hydration of small molecules For this month’s computational chemistry paper of the month, we have chosen to highlight Jazzy, a python package to calculate the strengths of hydrogen-bonds. As we all know the importance of hydrogen bond donors and acceptors in the drug discovery process. Within
Discovery of the Potent and Selective MC4R Antagonist PF-07258669 for the Potential Treatment of Appetite Loss In this Drug Annotation, the discovery of an antagonist of the melanocortin-4 receptor (MC4R) and clinical candidate: PF-07258669 is described. MC4R signalling is responsible for the regulation of food intake via the suppression of appetite. Inhibition of this target
MCPairs v1.9 release is automatically available to all users: MCPairs version 1.9 went live last weekend. All Online users are upgraded to the new platform, and all new tools are available to everyone. On logging on you will notice the change in the layout of the dashboard as CoreDesign® has been added. This joins RuleDesign®
Med Chem Paper of the Month – Jan/Feb 2023 This paper is a fine exhibition of multi-parameter optimisation that resulted in the candidate drug: MK-8189, currently undergoing phase II clinical trials for the treatment of schizophrenia. Discovery of MK-8189, a Highly Potent and Selective PDE10A Inhibitor for the Treatment of Schizophrenia Schizophrenia is a debilitating
Exposing the Limitations of Molecular Machine Learning with Activity Cliffs J. Chem. Inf. Model. 2022, 62, 5938−5951 The title of this paper pulled in my attention immediately. The authors performed a comprehensive study of the ability of ML and DL to predict the larger drops in potency that can occur with small structural changes. Activity
Design and Structural Optimization of Orally Bioavailable SOS1 Inhibitors for the Treatment of KRAS-Driven Carcinoma J. Med. Chem. 2022, 65, 15856−15877 This is a biased pick – we wrote a review on SOS1 inhibitors a year or so ago – so there you go [https://doi.org/10.1080/13543776.2021.1952984]. At the start of my career the pharma company I
