Pharmacophore-Based Virtual Screening to Discover New Active Compounds for Human Choline Kinase a1

Choline kinase (CK) catalyses the transfer of the ATP gamma-phosphate to choline to generate phosphocholine and ADP in the presence of magnesium leading to the synthesis of phosphatidylcholine. Of the three isoforms of CK described in humans, only the a isoforms (HsCK alpha) are strongly associated with cancer and have been validated as drug targets to treat this disease. Over the years, a large number of Hemicholinium-3 (HC-3)-based HsCK alpha biscationic inhibitors have been developed though the relevant common features important for the biological function have not been defined. Here, selecting a large number of previous HC-3-based inhibitors, we discover through computational studies a pharmacophore model formed by five moieties that are included in the 1-benzyl-4-(N-methylaniline) pyridinium fragment. Using a pharmacophore-guided virtual screening, we then identified 6 molecules that showed binding affinities in the low mM range to HsCK alpha 1. Finally, protein crystallization studies suggested that one of these molecules is bound to the choline and ATP-binding sites. In conclusion, we have developed a pharmacophore model that not only allowed us to dissect the structural important features of the previous HC-3 derivatives, but also enabled the identification of novel chemical tools with good ligand efficiencies to investigate the biological functions of HsCK alpha 1

Choline kinase active site provides features for designing versatile inhibitors

© 2014 Bentham Science Publishers. Choline kinase (CK) is a homodimeric enzyme that catalyses the transfer of the ATP γ-phosphate to choline, generating phosphocholine and ADP in the presence of magnesium. Several isoforms of CK are present in humans but only the HsCKα has been associated with cancer and validated as a drug target to treat this disease. As a consequence a large number of compounds based on Hemicholinium (HC-3) have been described. Two compounds, previously reported to inhibit the human enzyme, have recently been shown to inhibit P. falciparum CK (PfCK) and therefore their potential applications might be anticipated to other pathogens. Herein, using molecular dynamic simulations, we have firstly observed that the ATP and the choline binding site of different CK in pathogens and human are conserved, suggesting that previous compounds inhibiting the human enzyme may also interact with CKs from different pathogens. We have substantiated such observation with experimental assays showing that HsCKα1, PfCK and CpCK bind to two compounds with distinct structural features in the low μM range. Collectively, these results uncover similarities among the choline kinase binding site from different pathogenic species and the human enzyme, highlighting the feasibility of designing novel inhibitors based on the choline binding pocket.Peer Reviewe

Road towards development of new antimalarial: organelle associated metabolic pathways in Plasmodium as drug targets and discovery of lead drug candidates

Malaria remains a global threat with millions of deaths annually. Emergence of parasite strains resistant to widely used antimalarials, including the artemisinin combination therapy (ACT), and the absence of an effective vaccine makes treatment of malaria difficult than ever before. The need of the hour is to re-evaluate the chemotherapeutic approach and to identify new drug targets and develop new pharmacophores against the parasite. An important approach for antimalarial drug discovery is to understand critical metabolic pathways in the parasite which may help us to identify critical targets in the parasites and design specific inhibitors for these targets. Here, we have discussed proteins and pathways in different parasite organelles, i.e. apicoplast, mitochondrial and food vacuole, which have been suggested as potential drug targets; these unique parasite proteins can be targeted to develop new and novel antimalarials. In addition, we have also discussed several antimalarial projects currently under different stages of drug development pipeline. These promising antimalarial compounds have the potential to overcome multidrug resistance. Ongoing global efforts to develop new antimalarials and to identify drug targets suggest a promising future on malaria elimination and eradication