Totally drug resistant TB

One of the biggest problems in Tuberculosis (TB) therapy nowadays is that patients have to take antibiotics for up to 9 months. As many patients feel better before this time, they prematurely stop their treatment, leaving pools of the most drug-resistant M. tuberculosis in their lungs. This contributes to the emergence of complete drug resistance in future patients.

In the past few years, strains of drug resistant Mtb have become prevalent. In fact, resistance is so wide spread that it is now being classified as multi-drug resistant (MDR-TB) and extreme-drug resistant (XDR-TB). Two of the world’s most populous countries, India and China, account for more than 50% of the world’s MDR-TB cases.

Recent reports have also confirmed a new strain of existing Mtb which is completely untreatable and has been designated as Totally drug resistance TB (TDR-TB). Indeed, strains of Mtb have even evolved resistance to all major available anti-TB drugs. India (2012) is the third country in which a total drug-resistant form of the TB has emerged, following cases documented in Italy in 2007 and Iran in 2009. There is a need for a more readily available treatment that is effective against both sensitive and drug-resistant strains of M. tuberculosis is evident.

Nano reactions

Recently, nanoporous materials have emerged as important and efficient heterogeneous catalysts for the organic transformations owing to their excellent textural characteristics including high surface area, large pore volume, and uniform pore size distribution, and its simplicity in workup and recyclability. The pore diameters are chosen to control the access of molecules to the catalytic reaction sites located inside the porous cavities. Only the molecules of certain sizes and chemical properties are selected and guided to the reaction centers where they are efficiently transformed to the desired products.

What's a PhD worth?

Here's another article in the nature that makes some good points about the worth of PhD.

"The number of science doctorates earned each year grew by nearly 40% between 1998 and 2008, to some 34,000, in countries that are members of the Organisation for Economic Co-operation and Development (OECD). The growth shows no sign of slowing: most countries are building up their higher-education systems because they see educated workers as a key to economic growth. But in much of the world, science PhD graduates may never get a chance to take full advantage of their qualifications"

PhD program use to be for science-loving driven people and the world want more innovation from academic science to solve the problems.

Mycobacteria and the great wall

Mycobcaterial cell wall is unique, thick waxy and hydrophobic in nature, which ensures its survival inside human macrophages by resisting oxidative damages.The waxy, highly impermeable nature of the wall provides the required defense mechanism against antibiotic agents, and the host organisms. A key component of the cell wall is mycolic acids. Mycolic acid  accounts up to 60% of the dry weight of the organisms which means that most percentage of mycobacteria is a cell wall.  Thorough understanding of the influence of polarity on the drug penetration in to highly impermeable mycobacterial cell wall will guide us to improve permeability.

The permeation ability of a lipophilic molecule is inversely related to the fluidity of the cell wall, which decreases as the length of fatty acids in the mycolic acids layer increases. The permeability barrier presented by this cell envelope is also thought to be a reason why many common antibiotics are ineffective against mycobacteria. Lipophilic drugs, such as fluoroquinolones or rifamycins, pass more easily through the lipid-rich cell wall and thus are more active.

It is clear that, depending on the library screens towards compounds with a particular physicochemical parameter could actually be detrimental and decrease the diversity of finding new anti-TB drugs.

Enoyl reductase: One target, Two major Global Threats

Tuberculosis and Malaria are two major global threats both account 5 million deaths annually (mostly in poor countries). Despite the worldwide ravages of Tuberculosis and Malaria, chemotherapeutic regimens against these two diseases have remained largely unchanged. There is an urgent need to develop novel, effective, and affordable drugs to treat both diseases because resistance has developed or is developing to existing therapy. Scientists around the world are seeking new ways to combat the two opportunistic pathogens.

Mycobacterium tuberculosis and Plasmodium Falciparum responsible both organisms share enzymatic components of the type II fatty acid biosynthetic pathway (FAS-II). Enoyl acyl carrier protein reductase (ENR), is one of the key type II enzyme, has been repeatedly validated as an effective antimicrobial target (eg INH, diazoborines , triclosan , and thiolactomycin)

Triclosan, the ENR inhibitor showed very good activity against both organisms. Targeting ENR with new class of compounds may yield new Drug for the use against these devastating pathogens

The Future of Drug Discovery

 The new technologies promise to fill drug development pipeline with small molecule candidates is unfulfilled, so pharmaceutical industry is currently undergoing rapid changes, they are moving aggressively into large molecule drug development.

"Drug space” that is not part of the current drug development includes non-Lipinski NCEs, nanomedicines, nucleic acid-based drugs etc will include in future. One of the major Challenges for medicinal chemist is small molecule inhibitors of protein-protein interactions.

Toxicophores Simplified

Bottom of the pyramid

 Indian patients no longer have to wait for the drug to become generic. Recently BMS and Astra Zeneca launched their new oral pill Saxagliptin (DDP 4 inhibitors ) to treat type 2 diabetes in India, less than one year after its US approval. India is the first Asian country where the drug is available at affordable price which is 1/5 of its US cost


Pharma Companies are now realizing that there is tremendous opportunity in emerging markets, not only because they entail low operating costs but also because of the fast growing middle class population, they are emerging as a huge market for global products. As the economy grows life style associated diseases grow along with it, Therefore companies try to launch drugs for these life style related diseases such as diabetes. Forecasts suggest 50% of business will be in those markets by 2020. Acquisition of Daichi to Ranbaxy and Abbot by Piramals make it clear that big pharma companies want to make a strong market presence in India.

“Rather than trying to find a use for approved medicines that were developed for a non-Asian phenotype, the move is to discover and develop medicines specifically to treat Asian diseases,” explains Paul Bolno, VP of Oncology R&D, Business Development at GSK. Here is a Nature article

But it will take a long time for the local doctors here in Inida to stop giving the pills without any label and any expiry dates on it. (pic; which I was given by a local hospital for a mild fever, you have to remember the tablets by its color)

PhD fellowships

Faculty of Pharmaceutical Sciences, University of Copenhagen is announce that eight PhD fellowships will be available from 1 October 2010.You can read more about here

Kinase Inhibitors: beyond Oncology

We just published a paper in Bioorganic and Medicinal Chemistry, targeting Interleukin-2 inducible T-cell kinase (ITK) for treating Asthma.

Protein kinases are prime targets for anticancer therapies, but achieving specificity for a particular kinase is challenging because of their close structural similarities. This leads to unwanted side effects and the toxic outcome may also be due the result of tissue distribution of kinase inhibitors. Imatinib has been highly successful in the treatment of both chronic myelogenous leukaemia , gastrointestinal stromal tumours and other cancers,but associated with severe, cardio toxicity. Toxicity may be of less concern with oncologic kinases, What about non- cancer indications? Emerging clinical evidence (Nature Drug Discovery) of oral kinase inhibitors other than cancer shows that kinases could be effective at inhibiting number of inflammatory pathways.

Almost all the p38MAPK inhibitors having hepatotoxicity issue, SCIO 469 and Arry 797 initially developed for RA but went in to clinic for post operative dental pain , here the potential toxicity problems won’t show up because the drugs is used only for a very short time, Are BMS-582949 and VX 702 still in development? Hundreds of millions have been spent by different companies on P38 with nothing to show at the end.

Tasocitinib may be the first kinase inhibitor (JAK3) for non-oncology indication and the first oral DMARD for RA in a decade, if it successfully completes the Phase III