Aug
12
Mon
2013
Invited Talk: Strategies for Diseases/Target Selection for Drug Discovery and a Multi-Targeted Approach to Metabolic Disorder @ Sathyam Hall
Aug 12 @ 11:45 am – 12:10 pm

PradipPradip K. Bhatnagar, Ph.D.
Former President & Head, Daiichi Sankyo Life Science Research Centre, India


Strategies for Diseases/Target Selection for Drug Discovery and a Multi-Targeted Approach to Metabolic Disorder

Drug discovery and development is a high risk and expensive undertaking.  Although, technologies, such as, bioinformatics, genomics, high throughput screening and computer-aided design have helped identify targets, biomarkers, lead candidates and reduced the time required for  advancing an idea from  bench to clinic, but it still takes 10-12 years and costs approximately one billion dollars to bring a drug to market globally. Therefore, it is imperative that the strategies to reduce the risk and increase efficiency are carefully selected. In this presentation I would discuss strategies for selecting potential diseases, targets and provide an example of multi-targeted approach to metabolic disorder.

 

Aug
13
Tue
2013
Invited Talk: A cost-effective approach to Protein Structure-guided Drug Discovery: Aided by Bioinformatics, Chemoinformatics and computational chemistry @ Sathyam Hall
Aug 13 @ 11:15 am – 11:40 am

kalKal Ramnarayan, Ph.D.
Co-founder President & Chief Scientific Officer, Sapient Discovery, San Diego, CA, USA


A cost-effective approach to Protein Structure-guided Drug Discovery: Aided by Bioinformatics, Chemoinformatics and computational chemistry

With the mapping of the human genome completed almost a decade ago, efforts are still underway to understand the gene products (i.e., proteins) in the human biological and disease pathways.  Deciphering such information is very important for the discovery and development of small molecule drugs as well as protein therapeutics for various human diseases for which no cure exists.  As an example, with more than 500 members, the kinase family of protein targets continues to be an important and attractive class for drug discovery.  While how many of the members in this family are actually druggable is still to be established, there are several ongoing efforts on this class of proteins across a broad spectrum of disease categories.  Even though in general the protein structural topology might looks similar, there are issues with respect selectivity of identified small molecule inhibitors when, the lead molecule discovery is carried out at the ATP binding site.  As an added complexity, allosteric modulators are needed for some of the members, but the actual site for such modulation on the protein target can not resolved with uncertainty.  In this presentation we will describe a bioinformatics and computational based platform for small molecule discovery for protein targets that are involved in protein-protein interactions as well as targets like kinases and phosphatases.  We will describe a computational approach in which we have used an informatics based platform with several hundred kinases to sort through in silico and identify inhibitors that are likely to be highly selective in the lead generation phase.  We will discuss the implication of this approach on the drug discovery of the kinase and phosphatase classes in general and independent of the disease category.

 

Invited Talk: Pertubation of DNA topology in mycobacteria @ Acharya Hall
Aug 13 @ 11:50 am – 12:12 pm

NagarajaV. Nagaraja Ph.D.
Professor, Indian Institute of Science, Bengaluru, India


Perturbation of DNA topology in mycobacteria

To maintain the topological homeostasis of the genome in the cell, DNA topoisomerases catalyse DNA cleavage, strand passage and rejoining of the ends. Thus, although they are essential house- keeping enzymes, they are the most vulnerable targets; arrest of the reaction after the first trans-esterification step leads to breaks in DNA and cell death.  Some of the successful antibacterial or anticancer drugs target the step ie arrest the reaction or stabilize the topo -DNA covalent complex. I will describe our efforts in this direction – to target DNA gyrase and also topoisomerase1 from mycobacteria. The latter, although essential, has no inhibitors described so far. The new inhibitors being characterized are also used to probe topoisomerase control of gene expression.

In the biological warfare between the organisms, a diverse set of molecules encoded by invading genomes target the above mentioned most vulnerable step of topoisomerase  reaction, leading to the accumulation of double strand breaks. Bacteria, on their part appear to have developed defense strategies to protect the cells from genomic double strand breaks. I will describe a mechanism involving three distinct gyrase interacting proteins which inhibit the enzyme in vitro. However, in vivo all these topology modulators protect DNA gyrase from poisoning effect by sequestering the enzyme away from DNA.

Next, we have targeted a topology modulator protein, a nucleoid associated protein(NAP) from Mycobacterium tuberculosis to develop small molecule inhibitors by structure based design. Over expression of HU leads to alteration in the nucleoid architecture. The crystal structure of the N-terminal half of HU reveals a cleft that accommodates duplex DNA. Based on the structural feature, we have designed inhibitors which bind to the protein and affect its interaction with DNA, de-compact the nucleoid and inhibit cell growth. Chemical probing with the inhibitors reveal the importance of HU regulon in M.tuberculosis.

Invited Talk: Targeting aberrant cancer kinome using rationally designed nano-polypharmaceutics @ Acharya Hall
Aug 13 @ 2:05 pm – 2:29 pm

ManzoorManzoor K, Ph.D.
Professor, Centre for Nanoscience & Molecular Medicine, Amrita University


Targeting aberrant cancer kinome using rationally designed nano-polypharmaceutics

Manzoor Koyakutty, Archana Ratnakumary, Parwathy Chandran, Anusha Ashokan, and Shanti Nair

`War on Cancer’ was declared nearly 40 years ago. Since then, we made significant progress on fundamental understanding of cancer and developed novel therapeutics to deal with the most complex disease human race ever faced with. However, even today, cancer remains to be the unconquered `emperor of all maladies’. It is well accepted that meaningful progress in the fight against cancer is possible only with in-depth understanding on the molecular mechanisms that drives its swift and dynamic progression. During the last decade, emerging new technologies such as nanomedicine could offer refreshing life to the `war on cancer’ by way of providing novel methods for molecular diagnosis and therapy.

In the present talk, we discuss our approaches to target critically aberrant cancer kinases using rationally designed polymer-protein and protein-protein core-shell nanomedicines. We have used both genomic and proteomic approaches to identify many intimately cross-linked and complex aberrant protein kinases behind the drug resistance and uncontrolled proliferation of refractory leukemic cells derived from patients. Small molecule inhibitors targeted against oncogenic pathways in these cells were found ineffective due to the involvement of alternative survival pathways. This demands simultaneous inhibition more than one oncogenic kinases using poly-pharmaceutics approach. For this, we have rationally designed core-shell nanomedicines that can deliver several small molecules together for targeting multiple cancer signalling. We have also used combination of small molecules and siRNA for combined gene silencing together with protein kinase inhibition in refractory cancer cells. Optimized nanomedicines were successfully tested in patient samples and found enhanced cytotoxicity and molecular specificity in drug resistant cases.

Nano-polypharmaceutics represents a new generation of nanomedicines that can tackle multiple cancer mechanisms simultaneously. Considering the complexity of the disease, such therapeutic approaches are not simply an advantage, but indispensable.

Acknowledgements:
We thank Dept. of Biotechnology and Dept. Of Science and Technology,Govt. of India for the financial support through `Thematic unit of Excellence in Medical NanoBiotechnology’ and `Nanomedicine- RNAi programs’.

Manzoor

Aug
14
Wed
2013
Invited Talk: Nature Nurtures New Drug Discovery @ Acharya Hall
Aug 14 @ 10:10 am – 10:40 am
Former Vice-President, SPIC Pharmaceuticals, Tamil Nadu, India

The global healthcare scene of which the pharmaceutical industry and its products are integral components is today at the cross roads. The high and unaffordable costs of drug research with estimates of over 1 billion dollars for every new drug discovered and developed, the very low success rates, the high degree of obsolescence due to undesirable adverse drug reactions, the decline in the development pipeline of new drugs, patent expiries leading to generic competition and the public’s disillusionment with use of chemicals for human consumption   as drugs have all significantly contributed to the problems of this lifeline industry. The strategy adopted by the large R&D based Corporations  to get bigger and bigger through mergers and acquisitions to improve cost-effectiveness and productivity  of R&D has so far not  worked effectively. Consequently, one of the recent trends in healthcare, articulated by many experts is to look for  alternate or even complementary approaches to reduce the impact of rising costs of drugs on  healthcare. Various new strategies for drug discovery such as the use of  Natural Products especially medicinal plants  are being actively pursued by healthcare planners and providers.   Side by side, traditional systems of medicine whether from the oriental countries or the western nations are also having a serious relook to understand their usefulness in healthcare. To achieve its legitimate position in the healthcare scenario,  it is essential  to scientifically validate their claimed utility through appropriate and systematic research efforts including pre-clinical and clinical studies. In addition to their own use as medicines, knowledge on the Indian Traditional Medicines can be used as a platform for new drug discovery. The huge potential for carrying out  systematic R&D programs for new Drug Discovery  based on  natural products  and possible strategies  to realise them in the coming decades will be explained in this presentation.

MDNair

Invited Talk: New Drug R&D in India: Challenges & Opportunities @ Acharya Hall
Aug 14 @ 10:45 am – 11:30 am

RamaniRamani A. Aiyer, Ph.D., MBA
Principal, Shasta BioVentures, San Jose, CA, USA


New Drug R&D in India: Challenges & Opportunities

New drug discovery and development has become a global endeavor, with Western big pharmaceutical companies farming out more and more chemistry and biology research to Asia, particularly India and China. During the last decade, several Indian pharmaceutical companies have embarked on ambitious R&D programs, with slow but steady progress in developing new chemical / molecular entities. The Indian government has also made a strong commitment to promote innovation and entrepreneurship in the biotechnology sector. The first part of the talk will focus on a case study showing the entire process of discovery and development of a new drug recently launched for Rheumatoid Arthritis. We will then address the challenges of conducting innovative R&D in India and actions necessary to overcome them. The second part of the talk will make the case for developing Ayurvedic drug formulations for the Western / Global markets, again using the example of Rheumatoid Arthritis (Aamavaata). Ayurveda takes a holistic approach to disease diagnosis and therapy based on interactions among body type (prakriti), tri-doshas (three body humors), sapta-dhatus (seven tissues) and malas (excretions). The drugs prescribed are usually herbo-mineral formulations comprising multiple medicinal plants and / or metals. The manufacturing processes date back to Ayurvedic texts several thousand years old, and are compiled in the Ayurvedic Pharmacopeia. Also, the treatment modalities and drug formulations are “personalized” to fit different patient types, based on the holistic diagnoses mentioned earlier. There is a tremendous need to establish a sound basis for Ayurvedic drug discovery R&D for the modern world. We must find a scientific and ethical way to leverage the vast body of anecdotal and possibly retrospective data on patients undergoing Ayurvedic treatment. Combined with in vitro and in vivo biological data on Ayurvedic herbo-mineral formulations, the adoption of stringent manufacturing practices, and designing sound clinical trials to establish the safety and efficacy, India has a golden opportunity to expand the reach of Ayurvedic drugs into Western / Global medical practice.

Ramani

Delegate Talk: Intrinsic modulation of cytokine response by mycobacteria @ Acharya Hall
Aug 14 @ 11:35 am – 11:45 am
Delegate Talk: Intrinsic modulation of cytokine response by mycobacteria @ Acharya Hall | Vallikavu | Kerala | India

Sukhithasri V, Nisha N, Vivek V and Raja Biswas


The host innate immune system acts as the first line of defense against invading pathogens. During an infection, the host innate immune cells recognize unique conserved molecules on the pathogen known as Pathogen Associated Molecular Patterns (PAMPs). This recognition of PAMPs helps the host mount an innate immune response leading to the production of cytokines (Akira et al. 2006). Peptidoglycan, one of the most conserved and essential component of the bacterial cell wall is one such PAMP. Peptidoglycan is known to have potent proinflammatory properties (Gust et al. 2007). Host recognize peptidoglycan using Nucleotide oligomerization domain proteins (NODs). This recognition of peptidoglycan activates the NODs and triggers downstream signaling leading to the nuclear translocation of NF-κB and production of cytokines (McDonald et al. 2005). Pathogenic bacteria modify their peptidoglycan as a strategy to evade innate immune recognition, which helps it to establish infection in the host. These peptidoglycan modifications include O-acetylation and N-glycolylation of muramic acid and N-deacetylation of N-acetylglucosamine (Davis et al. 2011). Modification of mycobacterial peptidoglycan by N-glycolylation prevents the catalytic activity of lysozyme (Raymond et al. 2005). Additionally, mycobacterial peptidoglycan is modified by amidation for unknown reasons.

Here, we have investigated the role of amidated peptidoglycan in Mycobacterium sp in modulating the innate immune response. We isolated amidated peptidoglycan from Mycobacterium sp and non-amidated peptidoglycan from Escherichia coli. We made a comparative analysis of the cytokine response produced on stimulation of innate immune cells by peptidoglycan from E. Coli and Mycobacterium sp. Macrophages and whole blood were treated with peptidoglycan and the cytokines secreted into spent medium and plasma respectively were analyzed using ELISA. Our results show that peptidoglycan from Mycobacterium sp is less effective in stimulating innate immune cells to produce cytokines. This intrinsic modulation of the cytokine response suggests that mycobacteria modify their peptidoglycan by amidation to evade innate immune response.