RSC Medicinal Chemistry Blog

Human African trypanosomiasis, also commonly known as sleeping sickness, is a disease that leads to many deaths worldwide and is caused by protozoan parasites. When in the bloodstream these parasites can only produce the ATP (adenosine triphosphate) they need to survive via a glycolytic pathway, making this pathway essential for the parasite’s survival.

Phosphofructokinase is a kinase enzyme that phosphorylates fructose 6-phosphate in the glycolysis metabolic pathway, and is of central importance to carbohydrate metabolism. As such it is a very promising target for anti-trypanosomal drug design to treat sleeping sickness.

In this review Renata B. Oliveira et al. present a survey of recent literature regarding the structural and functional properties of phosphofructokinase as well as discussing its importance as a target in the development of selective therapeutics to treat Human African trypanosomiasis.

Read the full review here…

Phosphofructokinase: structural and functional aspects and design of selective inhibitors
Stefânia N. Lavorato, Saulo F. Andrade, Thaïs H. A. Silva, Ricardo J. Alves and Renata B. Oliveira
DOI: 10.1039/C2MD20122D

The phosphoinositide 3-kinase (PI3K) pathway is one of the most important signalling cascades in cancer. It has been well established as an attractive oncology target and inhibitors of PI3K have been suggested as promising agents for therapeutic intervention in cancer. Since the discovery of wortmannin and LY294002, the first compounds to inhibit PI3K, a vast number of inhibitors have been identified.

This review from Peng Wu and Yongzhou Hu, Zhejiang University, outlines the current landscape of the development of small molecule PI3K inhibitors, with a focus on structure–activity relationships (SAR) and discussion of co-crystal structures of the twenty-two molecules that are currently under clinical trials and newly emerged ones.

Read the review and let us know your thoughts by commenting below on this blog!

Small molecules targeting phosphoinositide 3-kinases
Peng Wu and Yongzhou Hu
DOI: 10.1039/C2MD20044A

Despite the tremendous advances in investigating the molecular mechanisms of Alzheimer’s disease and its relevance for society there is an alarming lack of drugs for clinical treatment. Apart from the NMDA antagonist memantine, several acetylcholinesterase inhibitors have been approved for symptomatic treatment of early stages of Alzheimer’s disease.

In this MedChemComm review Michael Decker and Ulrike Holzgrabe present a review of the different chemical structures of allosteric agonists and modulators of the muscarinic acetylcholine receptor subtype 1 (mAChR₁ or M₁) and their relevance for possible treatment of Alzheimer’s disease. The discussion also focuses on:

• Their design principles,
• Common structural properties,
• Unique features with regard to structure–activity relationships (SARs)

M₁ muscarinic cetylcholine receptor allosteric modulators as potential therapeutic opportunities for treating Alzheimer’s disease
Michael Decker and Ulrike Holzgrabe
DOI: 10.1039/C2MD20025B

Previously drug–receptor interactions have only been quantified in terms of their affinity and efficacy but recently the residence time has also been recognized to affect the clinical performance.

In this review Georges Vauquelin aims to try and help chemists to better evaluate the relevance of the kinetic data that may be obtained from compounds by discussing, with the aid of simulations, the different approaches to measure drug binding kinetics that are currently used to measure and calculate ligand–receptor dissociation kinetics, as well as covering some of the potential pitfalls associated with these methods.

To find out more about the finer points of drug–receptor residence times and see how this can help you, read the review now!

Determination of drug–receptor residence times by radioligand binding and functional assays: experimental strategies and physiological relevance
Georges Vauquelin
DOI: 10.1039/C2MD20015E