Monthly Archives: January 2011

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 , , , | 13 Comments

Working with Ion Channels

Two recent publications highlight the challenges inherent in the targeting of voltage-gated and ion-gated ion channels.  It is only in relatively recent times that technological advances (e.g. higher throughput patch-clamping) have opened up many of these targets to drug discovery … Continue reading

Posted in Ion Channel Blockers, Med Chem Strategy | Tagged , , , , , , , , , , , , , | 2 Comments

Review: Gamma-secretase modulators

An excellent review titled ‘γ-Secretase Modulators as Potential Disease Modifying Anti-Alzheimer’s Drugs’ has recently published in J.Med.Chem. The review gives some background to the disease and to the generally, although not universally, accepted hypothesis that amyloid plays a key role … Continue reading

Posted in Enzyme Inhibitors, Reviews | Tagged , , , , , , , , | 1 Comment

Discovery of Rivaroxaban (Factor Xa Inhibitor)

The discovery of novel anticoagulants, and the search for novel orally active agents in particular, has been a long and difficult journey.  However, the recent (2008) launches of Bayer’s Factor Xa inhibitor (Rivaroxaban, BAY 59-7939) and Boehringer Ingelheim’s Thrombin inhibitor … Continue reading

Posted in Enzyme Inhibitors, Launched Drugs | Tagged , , , , , , , , , , , , | 1 Comment

Structural Alert: Benzimidazoles

An informative letter, just published by a team from Novartis, highlights the risk of suitably substituted benzimidazoles acting as latent precursors to reactive ortho-iminoquinone species.  The example they report (see structure on left below) was Ames positive and exhibited time-dependent inhibition … Continue reading

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Atropisomerism in Drug Discovery

Following up on their earlier mini-review, the authors of this recent paper outline their work at Boehringer Ingelheim on developing methodology and strategies for dealing with the issue of atropisomerism in drug discovery.  The authors highlight the fact that, whilst the … Continue reading

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Discovery of PF-232798 (CCR5 Antagonist)

CCR5 antagonists prevent entry of HIV into host cells by binding to the CCR5 co-receptor and stopping the gp120-CD4 complex from making the crucial interaction with CCR5 that leads to fusion of the viral and host cell membranes (see Wikipedia article … Continue reading

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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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