Tag Archives: X-ray data

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

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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Halogen Bonding


Investigators at Roche recently published a communication describing a systematic study of halogen bonding effects in protein-ligand complexes of human Cathepsin L (hCatL).  They found that an inhibitor incorporating a 4-chlorophenyl moiety enhanced binding affinity by a factor of 13, … Continue reading

Posted in Computational Methods, Enzyme Inhibitors, Med Chem Strategy | Tagged , , , | 12 Comments

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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Improved PK profile through fluorine and deuterium incorporation


Compound (1) was identified by scientists at Merck as a potent Aurora kinase inhibitor with the potential to be useful in the treatment of various cancers.  In this paper the authors reveal that the basic amine which is key to good … 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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