In silico strategies on prion pathogenic conversion and inhibition from PrPC -PrPSc

Published ArticleTo date, various therapeutic strategies identified numerous anti-prion compounds and antibodies that stabilize PrPC, block the conversion of PrPC-PrPSc and increased effect on PrPSc clearance. However, no suitable drug has been identified clinically so far due to the poor oral absorption, low blood-brain-barrier [BBB] penetration, and high toxicity. Although some of the drugs were proven to be effective in prion-infected cell culture and whole animal models, none of them increased the rate of survival compared to placebo. Areas covered: In this review, the authors highlight the importance of in silico approaches like molecular docking, virtual screening, pharmacophore analysis, molecular dynamics, QSAR, CoMFA and CoMSIA applied to detect molecular mechanisms of prion inhibition and conversion from PrPC-PrPSc. Expert opinion: Several in silico approaches combined with experimental studies have provided many structural and functional clues on the stability and physiological activity of prion mutants. Further, various studies of in silico and in vivo approaches were also shown to identify several new small organic anti-scrapie compounds to decrease the accumulation of PrPres in cell culture, inhibit the aggregation of a PrPC peptide, and possess pharmacokinetic characteristics that confirm the drug-likeness of these compounds

Software for molecular docking: a review

Publshed ArticleMolecular docking methodology explores the behavior of small molecules in the binding site of a target protein. As more protein structures are determined experimentally using X-ray crystallography or nuclear magnetic resonance (NMR) spectroscopy, molecular docking is increasingly used as a tool in drug discovery. Docking against homologymodeled targets also becomes possible for proteins whose structures are not known. With the docking strategies, the druggability of the compounds and their specificity against a particular target can be calculated for further lead optimization processes. Molecular docking programs perform a search algorithm in which the conformation of the ligand is evaluated recursively until the convergence to the minimum energy is reached. Finally, an affinity scoring function, ΔG [U total in kcal/mol], is employed to rank the candidate poses as the sum of the electrostatic and van der Waals energies. The driving forces for these specific interactions in biological systems aim toward complementarities between the shape and electrostatics of the binding site surfaces and the ligand or substrate

The compound (3-{5-[(2,5-dimethoxyphenyl)amino]-1,3,4-thiadiazolidin-2-yl}-5,8-methoxy-2H-chromen-2-one) inhibits the prion protein conversion from PrPC to PrPSc with lower IC50 in ScN2a cells

Published ArticlePrion diseases are fatal neurodegenerative disorders of the central nervous system characterized by the accumulation of a protease resistant form (PrPSc) of the cellular prion protein (PrPC) in the brain. Two types of cellular prion (PrPC) compounds have been identified that appear to affect prion conversion are known as Effective Binders (EBs) and Accelerators (ACCs). Effective binders shift the balance in favour of PrPC, whereas Accelerators favour the formation of PrPSc. Molecular docking indicates EBs and ACCs both bind to pocket-D of the SHaPrPC molecule. However, EBs and ACCs may have opposing effects on the stability of the salt bridge between Arg156 and Glu196/Glu200. Computational docking data indicate that the hydrophobic benzamide group of the EB, GFP23 and the 1-(3,3-dimethylcyclohexylidene)piperidinium group of the ACC, GFP22 play an important role in inhibition and conversion from SHaPrPC to SHaPrPSc, respectively. Experimentally, NMR confirmed the amide chemical shift perturbations observed upon the binding of GFP23 to pocket-D of SHaPrPC. Consistent with its role as an ACC, titration of GFP22 resulted in widespread chemical shift changes and signal intensity loss due to protein unfolding. Virtual screening of a ligand database using the molecular scaffold developed from the set of EBs identified six of our compounds (previously studied using fluorescence quenching) as being among the top 100 best binders. Among them, compounds 5 and 6 were found to be particularly potent in decreasing the accumulation SHaPrPSc in ScN2a cells with an IC50 of 35 mM and 20 mM

The compound (3-{5-[(2,5-dimethoxyphenyl)amino]-1,3,4-thiadiazolidin-2-yl}-5,8-methoxy-2H-chromen-2-one) inhibits the prion protein conversion from PrPC to PrPSc with lower IC50 in ScN2a cells

Published ArticlePrion diseases are fatal neurodegenerative disorders of the central nervous system characterized by the accumulation of a protease resistant form (PrPSc) of the cellular prion protein (PrPC) in the brain. Two types of cellular prion (PrPC) compounds have been identified that appear to affect prion conversion are known as Effective Binders (EBs) and Accelerators (ACCs). Effective binders shift the balance in favour of PrPC, whereas Accelerators favour the formation of PrPSc. Molecular docking indicates EBs and ACCs both bind to pocket-D of the SHaPrPC molecule. However, EBs and ACCs may have opposing effects on the stability of the salt bridge between Arg156 and Glu196/Glu200. Computational docking data indicate that the hydrophobic benzamide group of the EB, GFP23 and the 1-(3,3-dimethylcyclohexylidene)piperidinium group of the ACC, GFP22 play an important role in inhibition and conversion from SHaPrPC to SHaPrPSc, respectively. Experimentally, NMR confirmed the amide chemical shift perturbations observed upon the binding of GFP23 to pocket-D of SHaPrPC. Consistent with its role as an ACC, titration of GFP22 resulted in widespread chemical shift changes and signal intensity loss due to protein unfolding. Virtual screening of a ligand database using the molecular scaffold developed from the set of EBs identified six of our compounds (previously studied using fluorescence quenching) as being among the top 100 best binders. Among them, compounds 5 and 6 were found to be particularly potent in decreasing the accumulation SHaPrPSc in ScN2a cells with an IC50 of 35 mM and 20 mM

Molecular docking of thiamine reveals similarity in binding properties between the prion protein and other thiamine-binding proteins

Prion-induced diseases are a global health concern. The lack of effective therapy and 100 % mortality rates for such diseases have made the prion protein an important target for drug discovery. Previous NMR experimental work revealed that thiamine and its derivatives bind the prion protein in a pocket near the N-terminal loop of helix 1, and conserved intermolecular interactions were noted between thiamine and other thiamine-binding proteins. Furthermore, water-mediated interactions were observed in all of the X-ray crystallographic structures of thiamine-binding proteins, but were not observed in the thiamine-prion NMR study. To better understand the potential role of water in thiamine-prion binding, a docking study was employed using structural X-ray solvent. Before energy minimization, docked thiamine assumed a "V" shape similar to some of the known thiamine-dependent proteins. Following minimization with NMR-derived restraints, the "F" conformation was observed. Our findings confirmed that water is involved in ligand stabilization and phosphate group interaction. The resulting refined structure of thiamine bound to the prion protein allowed the 4-aminopyrimidine ring of thiamine to \u3c0-stack with Tyr150, and facilitated hydrogen bonding between Asp147 and the amino group of 4-aminopyrimidine. Investigation of the \u3c0-stacking interaction through mutation of the tyrosine residue further revealed its importance in ligand placement. The resulting refined structure is in good agreement with previous experimental restraints, and is consistent with the pharmacophore model of thiamine-binding proteins. \ua9 2013 Springer-Verlag Berlin Heidelberg.Peer reviewed: YesNRC publication: Ye