Tag Archives: Structure Based Design

MDM2-p53 protein-protein interaction inhibitors


The successful development of inhibitors of protein-protein interactions remains a formidable challenge for medicinal chemists. An excellent review highlights some successes in this field and ascribes the low tractability of these targets to: The large contact surfaces between proteins (~1,500–3,000 … Continue reading

Posted in Med Chem Strategy, Reviews | Tagged , , , , , , , , | 5 Comments

GPCR structure and modeling


A recently published letter from scientists at Boehringer Ingelheim nicely summarizes recent advances in our understanding of G protein-coupled receptor (GPCR) structure and function. X-ray structures of the inactive forms of bovine rhodopsin (2000), β2 adrenergic receptor (2007 – with antibody … Continue reading

Posted in Computational Methods, GPCR ligands | Tagged , , , , , , , , , , | 1 Comment

Discovery of PF-04691502 (PI3K/mTOR dual inhibitor)


Rapamycin and it’s analogues (or rapalogues e.g. CCI-779) modulate the phosphatidylinositol 3-kinase (PI3K) signalling cascade by binding to an allosteric site on the mTORC1 complex (Mammalian target of rapamycin (mTOR), a class IV PI3K protein kinase, forms two functional complexes, … Continue reading

Posted in Clinical Candidates, Enzyme Inhibitors, Kinase Inhibitors, Kinases, Med Chem Strategy | Tagged , , , , , , , , , , , , , , , , , , , , , , , | Leave a comment

Structure-based design of BACE inhibitors


In a recent post the difficulties of developing drug-like and CNS penetrant inhibitors of β-secretase (BACE-1 or ASP-2) were hinted at (a detailed account of the state of the art can be found in this book).  Many of the reported inhibitors … Continue reading

Posted in Computational Methods, Enzyme Inhibitors, Med Chem Strategy | Tagged , , , , , , , , , , , , , , | 1 Comment

TAK-733 & CH4987655 (Allosteric MEK Inhibitors)


The mitogen-activated protein kinase (MAPK) signalling cascade is one of the key pathways regulating cell proliferation and differentiation and aberrant activation of this pathway is implicated in a number of cancers. Targeting components of the cascade thus has the potential … Continue reading

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PoseView


Workers at the Center for Bioinformatics, University of Hamburg recently published an article describing a freely accessible web-based application (PoseView) which automatically generates two-dimensional diagrams of macromolecular complexes illustrating the key ligand-protein interactions.   In the article the authors describe the … Continue reading

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Characterisation of p38 switch pocket inhibitors


Doramapimod (BIRB-796), from Boehringer Ingelheim, was the first reported  inhibitor of p38 which did not bind to the canonical ATP site.  This opened up the prospect of allosteric inhibition of kinases as a viable approach to identifying novel drug candidates. This … Continue reading

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