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

Modelling P-gp efflux may help us design better molecules   In order to treat disorders of the central nervous system (CNS), it is essential to design molecules that can cross the blood-brain barrier (BBB), a layer of tightly packed endothelial cells rich in P-glycoprotein (P-gp) efflux pumps that protect the CNS from circulatory chemicals. Designing

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

The Importance of Tracking "Missing' Metabolites: How and Why? Throughout the course of in-vivo studies, the task of tracking where a drug goes and what it does after entering a living system is, of course, a routine activity for Medicinal Chemists and DMPK Scientists. The data generated will inform the likely outcome of drug dosing

Machine Learning Strategies for Reaction Development: Toward the Low-Data Limit This useful perspective article discusses many recent attempts at applying machine learning strategies (particularly transfer and active learning) to reaction improvement and discovery. The authors present many of the examples where researchers have sought to apply these methods and achieve a balanced perspective on the

Discovery of an Oral, Beyond-Rule-of-Five Mcl‐1 Protein−Protein Interaction Modulator with the Potential of Treating Hematological Malignancies. In this paper, researchers from Janssen Pharmaceuticals were searching for a bespoke inhibitor of myeloid cell leukemia 1 (Mcl-1), which is among a family of proteins that regulate apoptosis, and is over-expressed in a number of hematological cancers and

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