In-Silico screening of Pleconaril and its novel substituted derivatives with Neuraminidase of H1N1 Influenza strain

Syed HUSSAIN Basha and R NALINI Prasad

For all author emails, please log on.

BMC Research Notes 2012, 5:105 doi:10.1186/1756-0500-5-105

Published: 17 February 2012

(Abstract (provisional)

Background

Neuraminidase (NA) is a prominent surface antigen of Influenza viruses, which helps in release of viruses from the host cells after replication. Anti influenza drugs such as Oseltamivir target a highly conserved active site of NA, which comprises of 8 functional residues (R118, D151, R152, R224, E276, R292, R371 and Y406) to restrict viral release from host cells, thus inhibiting its ability to cleave sialic acid residues on the cell membrane. Reports on the emergence of Oseltamivir resistant strains of H1N1 Influenza virus necessitated a search for alternative drug candidates. Pleconaril is a novel antiviral drug being developed by Schering-Plough to treat Picornaviridae infections, and is in its late clinical trials stage. Since, Pleconaril was designed to bind the highly conserved hydrophobic binding site on VP1 protein of Picorna viruses, the ability of Pleconaril and its novel substituted derivatives to bind highly conserved hydrophobic active site of H1N1 Neuraminidase, targeting which oseltamivir has been designed was investigated. Result 310 novel substituted variants of Pleconaril were designed using Chemsketch software and docked into the highly conserved active site of NA using arguslab software. 198 out of 310 Pleconaril variants analyzed for docking with NA active site were proven effective, based on their free binding energy.

Conclusion

Pleconaril variants with F, Cl, Br, CH3, OH and aromatic ring substitutions were shown to be effective alternatives to Oseltamivir as anti influenza drugs.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

Common sleeping pills linked to early death

 

Common sleeping pills linked to early death 

Higher doses also linked to increased risk of cancer

 

 

People who take commonly prescribed sleeping pills may be four times 

more likely to die prematurely, according to the latest research.

High doses of sleeping pills also increased risk of cancer by about a third, 

said the researchers from the Scripps Clinic Viterbi Family Sleep Centre, California, 

and the Jackson Hole Centre for Preventative Medicine, Wyoming.

The study, published in the journal BMJ Open, analysed data on more than 10,500 men and women 

living in California who took a range of sleeping pills for an average of 2.5 years between 2002 

and 2007. Patient survival was then compared with that of over 23,500 people matched for age, 

sex and lifestyle but who had not been prescribed sleeping pills over the same period.

The drugs prescribed included benzodiazepines, 

such as temazepam and diazepam; non-benzodiazepines, 

such as zolpidem, zoplicone, and zaleplon; 

barbiturates and sedative antihistamines.

People prescribed up to 18 doses of pills a year were more than 3.5 times as 

likely to die as those prescribed none, the study found.

But those prescribed between 18 and 132 doses of pills were more than four times as 

likely to do die compared with people who had not been prescribed sleeping pills.

The risk of dying prematurely increased with increasing doses of sleeping pills, 

as those taking the most doses (132+ per year) were more than five times as likely to die 

as those prescribed none, the researchers found.

Those taking the highest number of doses were also 35 per cent more likely to be diagnosed 

with any type of cancer, which could not be explained by pre-existing poor health.

Although the findings showed a statistical association between taking sleeping pills 

with an increased risk of death, it still did not establish a cause of death, the researchers said.

They said it might be time to "reconsider whether even the short term use of hypnotics, 

as given qualified approval in National Institute for Health and Clinical Excellence [NICE] guidance, 

is sufficiently safe."

Some 2.8 million prescriptions were dispensed for temazepam and nearly 5.3 million 

for zopiclone in England in 2010.

Malcolm Lader, professor of clinical psychopharmacology at the Institute of Psychiatry at King's College London, 

said people should not panic as a result of the findings, as more studies were needed.

"I agree that these drugs do have problems but I find some of these results quite difficult to accept.

"The main one is that with 18 doses a year you have three times the mortality - that's quite incredible 

because you would have people dropping like flies.

"The study needs to be replicated in a different sample and I think we 

need to hold judgement until we have further studies.

"What we don't want is people stopping sleeping tablets and then going through 

a very disturbing period of insomnia.

"People should discuss this with their GP but should not under any 

circumstances stop taking their medication."