InsilicoScientist blogs: Digital world of Drug design and Discovery

Spicy hot long pepper could kill cancer cells

2011-07-23T00:20:00.006-04:00

Natural products have played a significant role in fighting cancer. Taxol and Vinca alkaloids are examples of currently approved natural product drug for the treatment of cancer. Many more natural products like curcumine, the active ingredient of South Asian spice turmeric, have been shown to possess anticancer properties. The latest addition to the list is a constituent of long pepper. Piperlongumine (PL), a constituent of the fruit of a pepper plant found in southern India and southeast Asia (Piper longum; തിപ്പലി, പിപ്പലി (tippali, pippali) in Malayalam) has been shown to possess anti-cancer properties. It selectively targets and kills cancer cells but leaving normal cells unharmed.

As a computational medicinal chemist, I was curious about the potential molecular targets of Piperlongumine. From the first look at the chemical structure, it appeared to have some similarity (trimethoxyphenyl group) to Colchicine, a tubuline targeting small molecule.

However the authors found that Piperlongumine acts differently in inducing ROS than the tubuline binding agent Taxol. The compound is reported to target the ROS stress-response pathway. A search to the PubChem chemical biology repository identified shows 22 positive assays results for the Piperlongumine (CID: 637858), mostly from the authors of this publication.

Out of curiosity, I performed an in silico analysis to list potential target using chemoinformatics and chemical biology tools. First I went to the PubChem and searched for chemically similar compounds (95% or more), then listed the positive bioassay results for all of the compounds. From there proceeded to the protein targets of the assays. That listed 14 potential targets.

1. TPA: Tim23p [Saccharomyces cerevisiae S288c] 222 aa protein DAA10558.1 GI:285814664
2. TPA: Tim10p [Saccharomyces cerevisiae S288c] 93 aa protein DAA06693.1 GI:285809906
3. nuclear receptor ROR-gamma [Mus musculus] 516 aa protein NP_035411.2 GI:188536040
4. LANA [Human herpesvirus 8] 1129 aa protein YP_001129431.1 GI:139472804
5. cellular tumor antigen p53 isoform a [Homo sapiens] 393 aa protein NP_000537.3 GI:120407068
6. RecName: Full=BRCA1-associated RING domain protein 1; Short=BARD-1 777 aa protein Q99728.2 GI:116241265
7. Microtubule-associated protein tau [Homo sapiens] 383 aa protein AAI14949.1 GI:92096784
8. E3 ubiquitin-protein ligase Mdm2 isoform MDM2 [Homo sapiens] 497 aa protein NP_002383.2 GI:89993689
9. protein Mdm4 isoform 1 [Homo sapiens] 490 aa protein NP_002384.2 GI:88702791
10. cytochrome P450 1A2 [Homo sapiens] 516 aa protein NP_000752.2 GI:73915100
11. Microphthalmia-associated transcription factor [Homo sapiens] 419 aa protein AAH65243.1 GI:40807040
12. aldehyde dehydrogenase 1 family, member A1 [Homo sapiens] 501 aa protein AAP35567.1 GI:30582681
13. serine/threonine kinase 33 [Homo sapiens] 514 aa protein CAC29064.1 GI:12830367
14. RecName: Full=Breast cancer type 1 susceptibility protein; AltName: Full=RING finger protein 53 1863 aa protein P38398.2 GI:728984

The interesting targets are Microtubule-associated protein tau , E3 ubiquitin-protein ligase Mdm2, Microphthalmia-associated transcription factor, BRCA1-associated RING domain protein 1 and cellular tumor antigen p53. Well, this is just a fun way to use Chemical biology and chemoinformatics for drug design.

Some SAR is listed in the US patent (US20090312373). It would be great to see more SAR of the compound analoges to study the pharmacophores.

It is high time that we carry out a comprehensive systematic scientific research on the properties of traditional medicines and their chemical components. The knowledge of our forefathers should be capaitalized by us to fight the deadly diseases like cancer.

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Selective killing of cancer cells by a small molecule targeting the stress response to ROS

Nature Volume: 475, Pages: 231–234 (14 July 2011) DOI:doi:10.1038/nature10167

http://www.nature.com/nature/journal/v475/n7355/full/nature10167.html

US Patent
http://www.freepatentsonline.com/20090312373.pdf

Piperlongumine
SMILES N1(C(C=CCC1)=O)C(/C=C/C2=CC(=C(OC)C(=C2)OC)OC)=O
http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=637858
http://www.indofinechemical.com/gnicart/details.aspx?catid=P-004&pid=13253
http://www.rdchemicals.com/chemicals.php?mode=details&mol_id=8163

Structural bioinformatics study: trimethoxyphenyl part in PDB
http://www.pdb.org/pdb/ligand/ligandsummary.do?hetId=SNY&sid=3P9I

Life science animations and videos

2011-07-19T00:27:00.000-04:00

The Inner Life of a cell: Musical

MITOCHONDRIA

BIOVISIONS AT HARVARD UNIVERSITY

http://multimedia.mcb.harvard.edu/

Nobel prize commitee recognize significance of Structure-based drug design

2009-10-07T19:22:00.005-04:00

Structural biology has evolved considerably after the first breakthrough in understanding the molecular structure of DNA in 1950's. Nobel prize was awarded to them (Physiology/Medicine, 1962) for such an incredible discovery. This year's (2009) Nobel prize for chemistry goes to Venkatraman Ramakrishnan, Thomas A. Steitz and Ada E. Yonath for their work on structural understanding of ribosomal machinery using X-ray crystallography. Nobel committee believe that this discovery is significant for the structure-based drug design of new antibiotics, especially since the emergence of bacterial resistance.

"Ramakrishnan, Steitz and Yonath have all imaged the molecular interactions between ribosomes and antibiotics, providing key data to help guide structure-based drug design of new antibiotics"

My thought here is "Will structure-based computational drug design methods bring some breakthrough discoveries in the next 20 years?"

Scientific investigation of Indian ancestry: South Indians and North Indians?

2009-09-23T20:22:00.001-04:00

Indian ancestry revealed : Nature News

Apparently, Indian population is an excellent study medium for genetic analysis considering the huge endogamous subdivisions of population.

"The researchers showed that most Indian populations are genetic admixtures of two ancient, genetically divergent groups, which each contributed around 40-60% of the DNA to most present-day populations"

"...whereas European ancestry is mostly carved up by geography, Indian segregation was driven largely by caste. "There are populations that have lived in the same town and same village for thousands of years without exchanging genes," says Reich..."

More studies like this might reveal interesting and useful patterns of genetic diseases/resistances, helping us to understand the human genome from clinical perspective.

Influence of protein shape and conformation on Drug Binding; Lock and key, Induced fit and beyond?

2009-08-20T12:10:00.001-04:00

Intrinsic Changes In Protein Shape Influence Drug Binding

"According to the classical view, known as "induced fit," drug binding causes a change in the target protein structure......But it now appears that a protein has many different conformations that are already available even without the presence of a binding molecule, which is called the ligand. The ligand attaches to the protein shape that allows it to fit well, and that close interaction can lead to effective inhibition of protein function...."

Well, the thought process was on the horizon for sometime...

PNAS Article

Why the Pfizer layoff? narrowing its research focus? Cardiovascular research abandoned.

2009-01-15T13:10:00.001-05:00

"The move comes after the company announced in September it was narrowing its research focus to six disease areas Alzheimer's, cancer, schizophrenia, pain, inflammation and diabetes"...

"Surprisingly, one of the areas abandoned was cardiovascular disease, where Pfizer had been a dominant player with its $13 billion-a-year cholesterol fighter Lipitor, the world's top-selling drug..."

Drugmaker Pfizer cutting up to 800 scientist jobs - washingtonpost.com

More drug approvals from FDA is a welcome sign

2009-01-14T14:21:00.002-05:00

More approvals are welcome. Industry accuses FDA for not being efficient. At the same time, one should not forget about incidents like Vioxx tragedy

FDA Approves More Drugs, Still Misses Deadlines

FDA Warns Consumers About Tainted Weight Loss Pills

2008-12-23T13:25:00.001-05:00

Health hazard from online pharmacies? See the FDA report published yesterday.

FDA Warns Consumers About Tainted Weight Loss Pills

Blogged with the Flock Browser

News: Computer Aided Drug Design in Cancer drug discovery

2008-12-21T16:01:00.001-05:00

Another news of Computer Aided Drug Design in Cancer drug discovery.

http://www.recordnet.com/apps/pbcs.dll/article?AID=/20080405/A_NEWS/804050326/-1/A_LIFE

Best selling drugs - Lists

2008-12-18T16:46:00.001-05:00

Two among the top selling 10 drugs are proteins while all others are small molecules. Are we expected to see more protein based drugs in the near future?

Ten Best-Selling Drugs Worldwide 2006

List of bestselling drugs - Wikipedia, the free encyclopedia

Blogged with the Flock Browser

Open source model in scientific research publising: A revisit to the financial future

2008-07-03T11:17:00.001-04:00

Nature has some news to tell the world about their rival PLoS (Public Library of Science). Open source publishing by PLoS thrives on charity funding. Does the business model needs a redesign of it's aims, goals and strategies? Or is it a cheap trick from scared Nature publishing? Judge yourself....

PLoS stays afloat with bulk publishing : Nature News

Blogged with the Flock Browser

The corrupted use of Photoshop in biomedical research

2008-06-18T15:55:00.000-04:00

Photoshop might be a "useful" program for many unscrupulous manipulation of research data if it doesn't make sense. Check this out
Researcher suspended for falsifying data : Nature News: "Researcher suspended for falsifying data"

Hopefully no one fell into pit following up with her research finding.
Yet nother disappointing story. Blame it on the tenure track reviews and peer-pressure!

"QSAR: dead or alive?": Journal of Computer-Aided Molecular Design

2008-01-23T13:06:00.000-05:00

SpringerLink - Journal Article: "QSAR: dead or alive?"

Another article analysing decline of use of QSAR in drug design. It happens that the previous similar article* also came from Bristol-Myers Squibb.

*http://pubs.acs.org/cgi-bin/abstract.cgi/jcisd8/asap/abs/ci700332k.html

Growth of the Asian health-care market: global implications for the pharmaceutical industry : Nature Reviews Drug Discovery

2008-01-18T12:08:00.000-05:00

Growth of the Asian health-care market: global implications for the pharmaceutical industry : Nature Reviews Drug Discovery

The stats says that India is one of the worse in Asia in health care.
Check the graphs at nature drug discovery reviews..

Re-engineered Gleevec reduces heart risks

2008-01-18T11:48:00.000-05:00

Re-engineered Gleevec reduces heart risks

Scientist at Rice-M. D. Anderson came up with a successful example of rational computer based drug design; yet another one in recent CADD approaches.

List of World’s Fastest Supercomputers

2008-01-17T19:26:00.000-05:00

30th Edition of TOP500 List of World’s Fastest Supercomputers Released, Big Turnover Among the Top 10 Systems | TOP500 Supercomputing Sites:

Finally India into the top 10 of supercomputing!!
Check the news...

"For the first time ever, India placed a system in the Top 10. The Computational Research Laboratories, a wholly owned subsidiary of Tata Sons Ltd. in Pune, India, installed a Hewlett-Packard Cluster Platform 3000 BL460c system. They integrated this system with their own innovative routing technology and achieved 117.9 TFlop/s performance."

Trends in the globalization of clinical trials : Article : Nature Reviews Drug Discovery

2008-01-17T18:26:00.000-05:00

Trends in the globalization of clinical trials : Article : Nature Reviews Drug Discovery

It's evident that clinical trials are among the top latest happening things in Indian pharmaceutical industry. In this nature article, India with 20% growth in clinical trials is ranked (16th) ahead of China (25th). But wait, China shows an amazing growth of 47%, the most by any countries. Keep watching, something is really happening around....

Patenting the drug targets: New horizon and new social/monetary impacts

2008-01-16T16:29:00.000-05:00

Reach-through claims for drug target patents: Rx for pharmaceutical policy :

When a major chunk of scientific community debate for a free world (GNU), here comes a new development; patent the targets and earn money through the drugs acting on it.. Who'll finally pay for it? The unfortunate patients..

However this will be a motivating news to the biologist/pharmacologist who work hard to find novel targets but who are usually least benefited in monetary terms. It is crucial to make a fool-proof patent law in this regard. Otherwise, it'll hinder not only the scientific freedom but also treatment availability to the poor suffering patients.

Ghost heart has a tiny beat : Nature News

2008-01-16T10:28:00.000-05:00

Ghost heart has a tiny beat : Nature News

SciFi's are going to be real!!
What will happen in next 20 years??..

The Trouble with QSAR (or How I Learned To Stop Worrying and Embrace Fallacy)

2008-01-14T14:01:00.000-05:00

The Trouble with QSAR (or How I Learned To Stop Worrying and Embrace Fallacy)

Interesting article!

The picture provided is hilarious :)

(*Image from ACS J. Chem. Inf. Model.)

The evolution of Computer Aided Drug Design.

2006-12-10T03:51:00.000-05:00

As with any other branch of science, Computer Aided Drug Design also evolved through decades.