Approaches to Discovery and Development of Natural Products as lead compounds 

There are multiple hit identification strategies, and new drugs come from many sources, both rational and brute force. The exploitation of drug prototypes has been reviewed extensively. Some have argued that starting with an old drug is the best way to find a new drug. This has been called selective optimization of side activities (SOSA). Thus, one starts with a diverse collection of marketed drugs in order to find and then optimize hits against new pharmacological targets. Because the starting points have already proved useful in man, the hits are guaranteed to be drug-like. A number of successful SOSA examples have been reported starting from sulfonamides, calcium channel blockers, beta blockers, antidepressants, neuroleptics, and so on. Despite the power of combinatorial chemistry and HTS, natural products still provide unique structural diversity. Natural molecules have intrinsic advantages, of course, having evolved alongside biological systems. Mother Nature had eons of a head start versus medicinal chemists. Thus, it might have been predictable that a large percentage, almost 30%, of the NCEs approved by the FDA between 1981 and 2002 were natural products or compounds derived from natural products. Natural products (or derivatives) with important therapeutic uses today include the antibiotic vancomycin, the anticholinergic scopolamine, and the opiate morphine, to name just a few.

 However, in recent years, natural products have gone out of favor in some circles, in part because they have been less compatible with other new technologies, such as HTS.

New drugs come from many sources including:

* Focused synthesis of new chemical structures

* Modification of old drugs (new analogs)

* New uses for old drugs (repositioning or repurposing)

* Endogenous substances found in humans;

* Natural products from non-human sources; and

* Random screening.

Though the field of combinatorial chemistry is still evolving, it has already made a mark on the industry.

                                                                                                     Hit identification strategies.

 The most commonly applied hit identification strategies today range from knowledge based approaches, which use literature- and patent-derived molecular entities, endogenous ligands or biostructural information, to the purely serendipity-based ‘brute force’ methods such as combinatorial chemistry and high-throughput screening.

Serendipity, Combinatorial chemistry and HTS play a major role in identification of lead molecules from natural products

In brief Drugs from Natural Sources can be identified by the following processes

1. Serendipity
2. random collection and screening of material
3. Exploitation of ethnopharmacological knowledge.
4. HTS – High Thoroughput Screening
5. Combinatorial chemistry.

Optimization of leads

Lead identification/optimization is the one of the most important steps in drug development. The chemical structure of the lead compound is used as a starting point for chemical modifications in order to improve potency, selectivity. Potency, efficacy and selectivity are not the only needed characteristics of a drug; the drug has to have certain pharmacokinetic parameters so as to be involved in further drug development Once a molecule is identified, the next step is to check its ADMET (Adsorption, Distribution, Metabolism, Excretion and Toxicity) properties. If the molecule has no toxicity and no mutagenicity either, it has potential for use as lead molecule. Further optimization gives better quality of lead molecules. These may subsequently be developed as drug(s)

New compounds that show promising therapeutics potential based on the biological activity are subject to further studies aimed at developing a promising pharmaceutical candidate for preclinical studies and clinical trials.

Optimization of leads basically involves the following goals

• Suitably altering the lead so as to improve the ADME characteristics of the drug
• improving pharmacokinetic characterization of Drugs

Optimization of a lead is also expected to remedy the following shortcomings by molecular manipulation which includes

• Freedom from mutagenicity

• Freedom from teratogenicity

• Chemical stability

• Synthetic or biological accessibility

• Acceptable cost

• Ability to patent

• Clinical efficacy

• Solubility

• Satisfactory taste

• Ability to formulate satisfactorily for administration

• Freedom from an idiosyncratic problem.

The Nobel prize in chemistry for the year 2013 was awarded jointly to Martin Karplus (Harvard University) , Michael Levitt (Stanford School of Medicine) and Arieh Warshel (University of Southern California) for “the development of multi-scale models for complex chemical systems”.

The fact that scientists these days can use computers to carry out experiments has yielded a much deeper understanding of how chemical processes play out. Computer models mirroring real life have become crucial for most advances made in chemistry today. Chemists earlier used to create models of molecules using plastic balls and sticks. Today, the modelling is carried out in computers.

Wayback in the 1970s, Martin Karplus, Michael Levitt and Arieh Warshel laid the foundation for the powerful programs that are used to understand and predict chemical processes.

The strength of the methods the trio have developed is that they are universal. They can be used to study all kinds of chemistry –  from the basic molecules of life to the complex industrial chemical processes enabling scientists to optimize solar cells, catalysts in motor vehicles and even drugs, to name a few.

Their methods have been devised basing on both classical and quantum physics. For example, in simulations of how a drug couples (DRUG interaction) to its target protein in the body, the software performs quantum theoretical calculations on those atoms in the target protein that are interacting with the drug. The remainder of the large protein is simulated using less demanding classical physics . In the present day computer has become a tool as important the test tube for a chemist. The Simulations are so perfect that they mimick the outcome of traditional experiments.

The Royal Swedish Academy of Sciences (RSAS) said “It is a tantalizing thought. The computer models that have been developed by the three Nobel laureates are powerful tools. Exactly how far they can advance our knowledge is for the future to decide”.

How many time have u tried copying from a PDF file and pasting into Word?

1. You did Ctrl+C from a PDF

2. And then you hit Ctrl+V into a word document hoping to get this

3. But you get this !!!

Read on.

Today we show a simple and cool way of copying from PDF to Word without the need for any PDF to Word converter (Most people use it for this)

i) First of all download this little piece of software called Auto Unbreak.

ii) Next Open the File Autounbreak.exe . Copy content from PDF and hit Paste inside the Auto unbreak application we just downloaded

iii) Next step hit the unbreak button

iv) Press Ok and then select Copy button

v) Then Open Word and Now just hit Ctrl+V

Congratulations its pasted perfectly…

Simple isn’t it? Don’t blame me if you didn’t come across this tool earlier. Share it with your friends . Save your time and others’ too

Note: A small appeal to all those who read my articles. Writing articles requires a lot deal of time (like this one). Although it seems simple a typical post takes around 3-4 hours to work. Pharmawiki as you can see is free of Ads and hence you know that we do not get any financial benefit . The only thing that keeps me going is your feedback. So please share posts with your friends, post in comments if you have any trouble and use the contact us form to bring our attention to a particular topic. We will be more than happy to help.

Writing a thesis is a nightmare for most of us. Sometimes the task is more daunting than even the actual research work. One is always worried about the mistakes that may creep. Managing of literature and the task of adding references, page no, Table no. , generating index of figures and tables and a plethora of things which seem unmanageable by a single person. However using the tools of the modern day we can make our task a lot simpler.

So for any Researcher the following tools are indispensable:

1. Google Scholar: Google Scholar is Google for scientific articles. Everyone knows the power of Google as it comes to web searching and trust me Google Scholar is as powerful. It offers a major boost to the way we search. This is quite useful when we want to write a literature review which needs gathering of lot of articles and Google Scholars helps us both in Quantity and Quality of the research articles we get.

   (P.S. Through Google Scholar if you are lucky enough you can get PAID articles for FREE!!!)

   Read more about Google Scholar here

    

2. Zotero: Zotero is a free citation/ reference manager. What it does? It makes an electronic list of all the articles we search and save. Also it enables to make note for every article. But wait that is not what we use Zotero for. Zotero is used to manage references. It helps us to use these references in our articles and also generate the references section (Bibliography at the end). All this is done without the need of numbering the articles or worrying about formatting each and every individual reference. What if you have formatted references in a particular way and your mentor/guide says “Hey the Author names should be italicized not bold“. With Zotero it’s just a matter of few minutes.

   (P.S. I had formatted about 200 references in less than 30 minutes using Zotero + Google Scholar)

3. Microsoft Word: Though people might wonder what is so special about Word, there are many features you could use to make article/thesis writing a breeze. The most useful being auto generating of List of Contents, List of Tables, and List of Figures. It saves us the effort of remembering numbers of tables/figures so that when phrases such as “as evident from TABLE??” crop up word automatically fills it. And most importantly the advanced formatting offers us with a good lot of control over the look and feel of the thesis.

   Suppose you wonder “what if my font size for all headings was increased a bit and they were underlined would it be nice?”. With Word it’s a matter of seconds.

More articles on how to use these resources are coming up. So keep watching our website or subscribe to our Facebook page…

Google has redefined the way we use the internet. It has also simplified the way we search for scientific articles and journals. Thanks to “Google Scholar”. Below we try to answer some of the basic questions you may have about using Google Scholar

Q.1) What is Google Scholar?

Google Scholar is Google’s search engine exclusively for Students and Research people who search for scientific journals and articles

Q.2) Why should i use Google Scholar?

Unlike most other databases (Sciencedirect, Elsevier) which confine themselves to a selected journals, Scholar searches across all the databases and journals. If a article was published it should be on Google Scholar.

Q.3) Is it free?

Yes like all other products of Google, this is a free service Click here Google Scholar

Q.4) Can i download paid articles from Google Scholar?

As earlier said Google is just a search engine. Your ability to download article depends on the subscription you / your college has. Most Universities have integrated Google Scholar and you can directly search and download articles directly from the college website.

Q.5) What about the free articles?

Free/ opensource articles / articles without copyright restrictions can be directly downloaded through Google Scholar.

Q.6) How will this really benefit me?

Google scholar uses the same technology as Google search. So the advantages

• You need not remember the EXACT name of the author/ article. Spelling mistakes are allowed and Google corrects you 🙂
• Searching for articles is a breeze. (Trust me i have used ScienceDirect , Pubmed, Springer and what not). It is the fastest method.
• You can save your searches

Q.7) Does Google Scholar work with EndNote?

Google Scholar works seamlessly with almost all the citation managers including  Zotero , Mendeley, EndNote, Refman etc etc etc. And you can directly import citations into these reference managers/ citation managers.

Excited? Give Google scholar a try at scholar.google.com

You will never want to Go back …

More articles coming up:

1. What is Zotero and how should i use it?

2. Using Zotero and Google Scholar together.

3. How to gather resources for a research article using Zotero?

4. How to format references for my thesis/ article?

More Information about Google Scholar can be found at these resources

1. http://www.lib.ncsu.edu/articles/google-scholar/

EMBASE,PUBMED, MICROMEDEX, NAPRALERT, PHARMAGKB are some of the popular pharmaceutical databases. Lets have a quick look at their services.

1. EMBASE
A very rich source of biomedical information from Elsevier Lifescience Solutions, EMBASE is a comprehensive database which is used by a majority of biomedical researchers worldwide. It allows the tracking and retrieval of information regarding diseases and drugs ranging for pre-clinical studies to important and critical information on toxicological studies. There are over 25 million records that are indexed with EMBASE and all of these have been taken from hundreds of peer reviewed journals. If you are in search of up to date information for your research, EMBASE is your likely destination.

Students, educators, physicians, pharmacists, information managers, clinicians and medical librarians are regular users of EMBASE because of its wide and in-depth coverage of data. It is a very good resource for especially those who are into clinical research and pharmacovigilance.

2. PubMed
A free to use database, maintained by the United States National Library of Medicine at National Institutes of Health, PubMed provides access to references on biomedical and life sciences information. It primarily accesses the MEDLINE (Medical Literature Analysis and Retrieval System Online, a.k.a MEDLARS online) database which has information collected from academic journals of pharmacy, nursing, medicine, dentistry, veterinary medicine and health care. It is a very widely used database to access full text articles which are freely available.

3. MICROMEDEX
This is another very important and widely used database by researchers from various domains. It is a product of Truven Health Analytics which is a very trusted brand in evidence based medicine references. It provides well referenced information on diseases, drugs, toxicology, alternative medicine, acute care etc to healthcare practitioners for making precise diagnosis and treatment plans.
One very unique service called the PDR Electronic Library is specifically targeted towards providing information on drugs approved by the FDA which includes side effects, drug interactions, recommended dosages, contraindications and much more.

Click here to know more about the usefulness of MICORMEDEX for Pharmacists.

4. NAPRALERT
If you are into natural product research, you will face some difficulties while searching for quality information as there are very few indexed resources which provide good information about traditional medicine. However, NAPRALERT has been a big boon for phytochemists and pharmacologists who are into testing of natural products as it is high on precise information about natural products which includes ethnopharmacology, biochemical and pharmacological information on extracts of organisms in situ, in vitro, in vivo as well as in humans.

As of today, NAPRALERT houses more than 200,000 reviews and research papers from all over the globe and also covers marine natural products. Ethnomedicinal information on almost 20,000 species is also available, which is a very rare achievement.

5. PharmaGKB
It stands for Pharmacogenomics Knowledgebase and is yet another database which is hardly known to researchers in the pharmaceutical field, but is very sophisticated in terms of the information provided. It is a very good soruce of information on genomic, genetic, cellular and molecular phenotype data and clinical records from people who have been a part of pharmacogenomic research studies. It has data pertaining to more than 3000 diseases, almost 20,000 genes and 2500 drugs as well as 53 pathways. Very useful for researchers in understanding the effect of genetic makeup in producing different reactions to drugs in different individuals.

Researchers are advised to visit these databases to collect latest biomedical information. We will keep posting about more pharmaceutical databases.