Research in chemistry at SNU is currently ongoing or under active development in the following broad research areas:
Chemical Biology, Molecular Toxicology, Chemical & Biological Crystallography
- Chemical biology
- Chemistry of nanomaterials
- Computational quantum chemistry
- Coordination Chemistry
- Green chemistry
- Medicinal chemistry
- Molecular Toxicology
- Polymer chemistry
- Structural Chemistry and Crystallography
- Supramolecular Chemistry
- Synthetic Organic Chemistry
The Chowdhury lab works in the interface of chemistry and biology trying to understand at the molecular level the effect of small organic molecules on biological systems. The goal is to elucidate the molecular mechanism of toxicity of drugs, pesticides and carcinogen suspect agents. Specifically, we are interested in the metabolism/biotransformation of these agents by various enzymes including P450s, formation of reactive intermediates, its interaction with DNA and proteins, and the mutational and/or toxicological consequences. The Chowdhury lab is currently studying a diverse array of compounds including thalidomide, ethylene dibromide, and various derivatives of 8-NO2-G (8-nitroguanine, 8-nitroguanosine, and 8-nitro-cyclicGMP). Thalidomide is a teratogen that has been recently approved for the treatment of multiple myeloma and leprosy, ethylene dibromide is an environmental toxicant, and 8-NO2-G compounds are detected in vivo at sites of chronic inflammation.
Another area of interest is the development of predictive biomarkers of toxicity of reactive intermediates. Bioavailability and particularly toxicity are two of the most common barriers in drug development today, and drug metabolism can influence both. As a result of toxicity, 16 out of 548 new chemical entities that were approved for the US market were subsequently withdrawn and 56 acquired black box warning. Predicting toxicity is thus an important issue in the development of pharmaceuticals as it is with pesticides, cancer suspects, environmental pollutants, and drugs of abuse. The mechanisms by which chemicals exert toxic effects are complex. Formation of "reactive metabolites" has been implicated as a major cause of toxicity or adverse drug reactions. Reactive metabolites may interact with cellular macromolecules resulting in various biological outcomes including mutations, inflammation, and alteration of gene expression, protein functions, and cellular metabolism that may lead to adverse effects. Alternatively, interaction of reactive metabolites with cellular macromolecules may also lead to detoxification. There is no simple correlation between reactive metabolite formation and toxicity, and therefore, conventional methods including covalent binding and thioether adduct formation are not sufficient to predict the toxicological outcome in vivo. There is a knowledge gap between the formation of reactive metabolites and toxicity. The goals are to understand the molecular mechanism of toxicity associated with reactive metabolites and, in the process, identify potential predictive molecular biomarkers of toxicity.
The proposed projects of the Chowdhury laboratory involve multidisciplinary basic research with translational values. The findings will have the potential to contribute not only in the field of drug development but also towards understanding the possible cause of certain cancers and their early detection or risk assessment.
Our research is mainly focused on bridging the gap between experimental and theoretical determinations of molecular properties, and the use of tools and methods from computational chemistry to inform aspects of modern crystallography. The interaction with (and critical assessment of) experimental data and results is always a significant component of our research. The research involves the extraction of physical, chemical and biological information, especially hydrogen bonds and intermolecular interactions in small molecules, amino acids and proteins using high-resolution X-ray, synchrotron and neutron diffraction data. Charge density analysis using high-resolution single-crystal X-ray diffraction data is now a mature branch of modern crystallography, which is now extended from small molecules to proteins. We are aiming to exploit this unique technique for
(i) quantitative studies of hydrogen bonding and electrostatic interaction energies in proteins (ii) exploring charge transfer mechanism in organic non-linear optical polymorphic materials (iii) halogen bonding interaction studies on small molecule drugs and materials with biological target and also we are working on Crystal Structure (polymorph) Predictions.
Students will have ample opportunities to work in these interdisciplinary projects combining experimental and theoretical approaches in chemical and biological systems.
Research in our laboratory is focused on two major areas: chemistry (Organic / Inorganic / nanomaterial) and biology, at the interface of chemistry and biology. Our aim is to understand the many roles that proteins play in physiological and pathological process and to use this knowledge to identify novel therapeutic targets for the treatment of complex diseases such as cancer, atherosclerosis and autoimmune diseases (AD) like multiple sclerosis (MS), type-1 diabetes (T1D) and arthritis. The goal is to develop the engineering solutions for those complex diseases and to achieve our goals we develop and apply new technologies that bridge the fields of chemistry and biology. A large variety of powerful tools are used to explore the chemistry–biology interface—a unique and exciting opportunity for students to engage in a number of existing multi-disciplinary research. Students will be exposed to a broad range of techniques in chemistry as well as biology research focused on organic, inorganic, nanomaterial and polymer synthesis, characterization tools, protein purification, gel electrophoresis, cell biology etc.
Cheminformatics, Theoretical and Quantum Chemistry
1) Autoimmune Diseases:
Autoimmune diseases (AD) result from a dysfunction of the immune system in which the body’s immune system mistakenly attacks and destroys its own organs, tissues, and cells. Physicians and scientists have identified so far more than 80 clinically distinct autoimmune diseases. A novel class of helper CD4+ T cells, called Th17, is critical for mucosal and epithelial host defense against extracellular bacteria and fungi. However, uncontrolled or inappropriate activation of Th17 cells is associated with the pathogenesis of numerous autoimmune diseases. Our laboratory is focused on designing and identifying small molecules which can selectively block the differentiation pathway of this pathogenic T cell and on studying the mechanisms associated with these molecules to understand more about this recently discovered T helper cells.
2) Target specific hormone delivery:
Multiple sclerosis (MS) is an example of chronic inﬂammatory demyelinating disease of the central nervous system (CNS) where major thyroid hormone receptor alpha (TRa) is expressed in higher amount. The effects of thyroid hormone (TH) are mediated at a cellular level by two different nuclear thyroid hormone receptor (TR) subtypes, TRa and TRb. Recently it has been shown that thyroid hormone treatment can improve remyelination in different MS experimental rodent models and suggested that TH treatment could be used as an effective therapeutic intervention in MS. On the other hand, THs have the potential for lipid lowering and antiobesity agents, but the lack of selectivity of naturally occurring agonists prohibits their use and thus arise safety concerns for clinical use. Therefore target-specific hormone delivery has an immense potential in the treatment of organ specific diseases including MS, obesity, and other organ related diseases, without any or diminished side effect. The goal in this project is targeted delivery of natural agonist to the different tissues to cure tissue specific diseases.
3) Development of ‘intelligent' systems for tumor and cardiovascular diseases:
Cardiovascular disease (CVD) has now become the number one killer in India and the leading cause of death worldwide. CVD is caused in large part by atherosclerosis. During the progression of atherosclerotic lesion, macrophages undergo activation, migration, differentiation, proliferation, and death. Therefore, intervention of macrophage activities has potential therapeutic application for the diagnosis and treatment of this particular disease. Our research is focusing on developing novel technologies for the detection and monitoring of cardiovascular diseases in their early stage to offer improved sensitivity, specificity, and cost-effectiveness. The philosophy of the chemical biology group is to discover new small molecules for a targeted function and apply our novel chemistry to biological problems of broader interest.
Computational and cheminformatics methods are increasingly used for the design and discovery of molecules with specific chemical and biological properties. The cheminformatics group has co-developed popular cheminformatics software for generating molecular properties and descriptors for quantitative structure-activity and structure-property relationships (QSAR/QSPR), thereby enabling macromolecules and large chemical, pharmaceutical and polymer fragment databases to be rapidly scanned for desirable combinations of physical, chemical, and physiological properties.
Some current directions include development of novel molecular descriptors for the prediction and interpretation of protein-ligand binding and protein similarity classification, for the design of polymers and nanomaterials with specific dielectric properties.
With the increasingly availability of inexpensive computational resources, large public repositories of chemical and biological data, and high-throughput assay technologies, it is now feasible to analyze the topological properties of large chemical and biological networks, such as drug similarity networks, molecular diversity libraries, chemical reaction networks, protein-protein and protein-drug interaction networks, using the methods of graph theory. Our work mapping the topology of chemical and biological networks can help identify the most promising regions of chemistry space for the purpose of lead optimization, and the potential for cross-reactivity of drugs.
Coordination and Supramolecular Chemistry
Our group has also been extending this cheminformatics approach to the materials realm, spanning polymeric materials, atomic clusters and nano alloys, in the search for improved materials with specific properties – an approach known as the Materials Genome Initiative.
Another long-standing research interest in the area of quantum chemistry is the computation of nonadiabatic couplings, and manifestations of the geometric phase. Applications include diverse problems ranging from the chemistry of inter-stellar molecules to the detailed mechanism of photosynthesis, vision and the physics of the insulating state.
Research in my group focuses on using modular, and tunable ultra-rigid building blocks in the development of structurally simple functional materials, e.g., molecular switches, fluorophores and sensors. For this purpose synthetic organic and coordination chemistry is used in combination with advanced spectroscopic and computational methods.
Our interest in controlling the luminescence property of the rigid building blocks having orthogonal donor-acceptor functionality has driven us to the development of new functional luminescence coordination complex materials that can be used in organic light emitting diode (OLED) application, single and multiphoton absorption study, and sensors.
The group is also developing new organic phase changeable supramolecular switching materials that will be explored in the optoelectronic applications, e.g., NLO, ferroelectricity, memory devices.
Organic and Polymer Chemistry, Green chemistry, Chemistry of nanomaterials
- Sustainable synthetic route for Bio-based polymers for composite (coatings and adhesive applications) and nano-composite applications (energy storage devices)
- Polymers and small molecules (organic and inorganic) for solar cells and OLEDs applications
- Nanomaterial synthesis and their structural modification
We work on the synthesis of metal nanoparticles through a sustainable methodology without recoursing to stressful methods. Additionally, simple organic ligands are chosen to stabilize the nanoparticles thus ensuring that the outcome can be targeted to benefit both prokaryotic and eukaryotic systems. Silver nanoparticles (AgNP) synthesized the laboratory are systematically analyzed for their efficacy towards microbes as well as specific cell lines to eventually heal tissue while having a high LD50 and LC50 value towards the targeted cell line.
Synthetic Organic and Medicinal Chemistry, Phenotypic Screening, Diversity Oriented & Asymmetric Synthesis
- Design and synthesis of anti-tubercular compounds using a fragment based drug design (FBDD) approach in particular targeting arabinosyltransferase.
- Exploring Carbohybrids as new class of bioactive molecules for anti-cancer therapy.
- Identification of new biomarker candidates for early detection of tuberculosis.
- Synthesis of highly functionalized and conformationally constrained bicyclic azasugars as glycosidase inhibitors.
- Probing signaling pathways in plants towards more biomass production.
- Identification and synthesis of new ligand in drug discovery project, as shown in the schematic representation.
Human brain cells (neurons) communicate with each other by releasing small chemical compounds called neurotransmitters. Monoamines such as serotonin, epinephrine, and dopamine are essential neurotransmitters released by our brain cells. The dysregulation of monoamine metabolism have been implicated in psychiatric disorder such as depression and in neurodegenerative disorders like Parkinson’s disease (PD) and Alzheimer’s disease (AD). According to the World Health organization (WHO) depression is now the fourth leading cause of disability worldwide and over 121 million people are affected by it. On the other hand, neurodegenerative diseases are amongst the most costly and devastating diseases that affect millions of people worldwide and it is estimated that by 2050 every 1 person in 85 will be affected by Alzheimer’s disease alone. In this project, we plan to tackle both psychiatric disorders and neurodegenerative diseases by selectively inhibiting two different isoforms of an enzyme-monoamine oxidase (MAO).
Depression and other psychiatric disorders occur when monoamine neurotransmitter level gets depleted in brain either by 1) reuptake of neurotransmitters back into neurons or by 2) breakdown of neurotransmitters by enzymes prior to reuptake back into the neuron. We are particularly interested in the breakdown processes of the monoamines that are catalyzed by monoamine oxidase (MAO). When MAO is overexpressed, the level of amines in brain significantly drops, which leads to psychiatric disorders such as depression. Therefore, inhibition of MAO activity is a useful mechanism to maintain optimum levels of monoamines and there is a great deal of interest in developing MAO inhibitors (MAOIs). MAO has two isoforms- MAO-A and MAO-B. MAO-A preferentially metabolizes serotonin, melatonin, epinephrine, and norepinephrine and MAO-A levels in the brain are elevated by an average of 34% in patients with major depressive disorder. Therefore, MAO-A is the preferred target to tackle depression and MAO-A inhibitors are preferably used as antidepressants.
On the other hand, MAOB mainly metabolizes dopamine (DA) and other less clinically relevant amines, and therefore, MAO-B inhibitors are not a preferred for treating depression. A recent report suggests that, with age, expression levels of MAO-B isoenzyme in neuronal tissue increase 4-fold. This overexpression of MAO-B results in an increment of dopamine metabolism and the production of hydrogen peroxide (H2O2). Overproduction of H2O2 leads to oxidative stress that may play a relevant role in the etiology of neurodegenerative diseases. As a result, MAO-B inhibitors may become useful as adjuvants for treating neurodegenerative diseases like Parkinson’s disease (PD) and Alzheimer’s disease (AD). This theory is further supported by the fact that transgenic mice lacking MAO-B show resistance to a mouse model of Parkinson's disease.
Developing selective inhibitors of MAO-A and MAO-B isoforms is challenging as they bear 70% sequence similarity. Most of the marketed MAO inhibitors are irreversible and non-selective and are associated with severe side effects. In this project, we plan to develop selective and reversible small molecule inhibitors of MAO isoforms. We plan to synthesize highly diverse small heterocyclic compounds with chiral centers at positioned at specific locations by using solid and solution phase synthesis and evaluate their monoamine oxidase inhibition ability and study the importance of chirality on their selectivity.
My research focuses on three aspects organic chemistry:
Recent Departmental Publications:
- Diversity Oriented Synthesis and phenotypic screening: Small molecules make excellent drugs because of their ability to modulate the functions of proteins in living systems. Our group combines diversity oriented synthesis along with phenotypic screening to identify such bioactive molecules (DOI: 10.1002/asia.201200385; 01203)
- Organocatalytic asymmetric synthesis: Discovery of novel reactions and ligands
- Organic Methodologies and total synthesis of natural products
- Ravi Kant Upadhyay, Navneet Soin, Susmita Saha, Anjan Barman, Susanta Sinha Roy, Materials Chem. Phys. (2015) DOI: 10.1016/j.matchemphys.2015.02.032
- G. Prabhu, S. Agarwal, V. Sharma, S. M. Madurkar, P. Munshi, S. Singh, S. Sen. A natural product based DOS library of hybrid systems, Eur. J. Med. Chem. 95, 41 - 48 (2015)
- Justin T. Foy, Debdas Ray, Ivan Aprahamian, Regulating signal enhancement with coordination-coupled deprotonation of a hydrazone switch, Chem. Sci. 6, 209 (2015)
- B. Zarychta, A. Lyubimov, M. Ahmed, P. Munshi, B. Guillot, A. Vrielink, C. Jelsch. “Ultra-high resolution crystal structure and charge density study of cholesterol oxidase”. Acta Crystall. D, 71, 954 (2015).
- G. Chowdhury, F.P. Guengerich, Characterization of Thioether-Linked Protein Adducts of DNA Using a Raney-Ni-Mediated Desulfurization Method and Liquid Chromatography-Electrospray-Tandem Mass Spectrometry, Curr. Protoc. Nucleic Acid Chem. 60:10.15.1-10.15.14 (2015) DOI: 10.1002/0471142700.nc1015s60
- V. Sharma, S. Agarwal, S. M. Madurkar, G. Dutta, P. Dangi, R. Dandugudumula, S. Sen, S. Singh, Diversity Oriented synthesis and activity evaluation of substituted bicyclic lactams as antimalarial against Plasmodium falciparum, Malaria J. 13, 467 (2014)
- N. Sukumar, M. P. Krein, G. Prabhu, S. Bhattacharya, S. Sen, Network Measures for Chemical Library Design, Drug Devel. Res. 75: 402–411 (2014)
- Pratibha Sharma, Swapnil Shukla, Bimlesh Lochab, Devendra Kumar, Prasun Kumar Roy, Microencapsulated cardanol derived benzoxazines for self-healing applications, Materials Lett. (2014) DOI: 10.1016/j.matlet.2014.07.048
- Bimlesh Lochab, Swapnil Shukla and Indra K. Varma, Naturally occurring phenolic sources: Monomers and Polymers, RSC Adv. 4, 21712 (2014)
- N. Sukumar, Ganesh Prabhu, Pinaki Saha, Applications of Genetic Algorithms in QSAR/QSPR modeling, Applications of Metaheuristics in Process Engineering, Eds: Jayaraman Valadi, Patrick Siarry (Springer, 2014) pp.315-324.
- Subhabrata Sen, Ganesh Prabhu, Chandramohan Bathula, Santanu Hati, Diversity Oriented Asymmetric Synthesis, Synthesis (2014) DOI: 10.1055/s-0033-1341247
- Pratibha Sharma, Swapnil Shukla, Bimlesh Lochab, Devendra Kumar, Prasun Kumar Roy, Microencapsulated cardanol derived benzoxazines for self-healing applications, Mater. Lett. 133, 266-268 (2014)
- Subhabrata Sen, Rajanikanth Mamidala, Surendra V Damerla, Y. L. N. Murthy, Rambabu Gundla and M. Thirumala Chary, Pyrrolidine and piperidine based chiral spiro and fused scaffolds via build/couple/pair approach, RSC Adv. (2014) DOI: 10.1039/c3ra47714b
- Carine Maaliki, Charles Gauthier, Olivier Massinon, Ram Sagar, Stéphane P. Vincent and Yves Blériot, Conformationally restricted glycoside derivatives as mechanistic probes and/or inhibitors of sugar processing enzymes and receptors, Carbohydrate Chem. 40, 418-444 (2014).
- Subhabrata Sen, Rajanikanth Mamidala, Rambabu Gundla and M. Thirumala Chary, Diversity Oriented Synthesis of macrocyclic diaryl ethers via Doetz Benzannulation, Asian J. Org. Chem., 2013, DOI: 10.1002/ajoc.201300125
- D. Manna, G. Roy, G. Mugesh, Antithyroid Drugs and their Analogues: Synthesis, Structure and Mechanism of Action. Acc. Chem. Res. 11, 2706 - 2715 (2013)
- G. Roy, P. N. Jayaram, G. Mugesh, Inhibition of Lactoperoxidase-catalyzed Oxidation by Imidazole-based Thiones and Selones: A Mechanistic Study, Chem. Asian J. 8, 1910 - 1921 (2013)
- G. Pilania, C. Wang, K. Wu, N. Sukumar, C. M. Breneman, G. A. Sotzing, R. Ramprasad, New Group IV Chemical Motifs for Improved Dielectric Permittivity of Polyethylene, J. Chem. Inf. Model. 53(4):879–886 (2013) DOI: 10.1021/ci400033h
- N. Sukumar, Ed. “A Matter of Density: Exploring the Electron Density Concept in Chemical, Biological, and Materials Sciences” (John Wiley, Hoboken, NJ, 2012). ISBN: 978-0-470-76900-3
- Parthapratim Munshi, Funding Agency: SERB/DST/EMR
Project Title: Quantitative Studies of Hydrogen Bonding and Electrostatic Interaction Energies in Proteins: Insights from Advanced Charge Density Analysis
Duration: 3 Years from May 2015
Budget amount: ~₹ 60 Lakhs
- Parthapratim Munshi; Co-PI: Dr. Alison Edwards, Funding Agency: Bragg Institute, Australian Nuclear Science and Technology Organisation (ANSTO, Australia)
Project Title: Exploring Charge Transfer Mechanism in Organic NLO (Polymorphic) Materials: Insights from Charge Density Analysis (ID 3822) Neutron beam time at KOALA instrument
Duration: May 11 - 16, 2015.
Budget amount: $AU 40,200 (~₹ 20 Lakhs)
- Gouriprasanna Roy, Funding Agency: DST SERB
Project Title: Detoxification of Organomercury Compounds: Enzyme Mimetic Studies to Understand the C‐Hg Bond Activation by Organomercurial Lyase.
Duration: 3 years - 2014-2017
Budget amount: ₹ 51 lakhs
- Shailja Singh (DLS), Subhabrata Sen, Funding Agency: DBT Pilot Project Grant for Young Investigators in Cancer Biology
Project Title: Diversity oriented synthesis and biological evaluation of spiroindolines, spiroindolones and spiroquinolines as novel molecules for breast cancer treatment.
Duration: 3 years - 2014-2017
Budget amount: ₹ 25 Lakhs
- Shailja Singh (DLS), Subhabrata Sen, Funding Agency: CSIR
Project Title: Identifying a small molecule for malaria by Diversity Oriented Synthesis of natural product inspired scaffolds
Duration: 2 Years
Budget amount: ₹ 16.7 Lakhs
- Bimlesh Lochab, Funding Agency: DST SERB, Engineering Division, Young Scientist Scheme
Project Title: Halogen free flame retardant (FR) Polybenzoxazine (PBz) resins based on agricultural biomass.
Duration: 3 years - 2014-2017
Budget amount: ₹ 28.64 Lakhs
- Bimlesh Lochab, Funding Agency: DST SERB
Project Title: Biobased Polybenzoxazine Resins Synthesized from Agricultural Biomass for Composite Applications.
Duration: 2 years - 2014-2016
Budget amount: ₹ 18 Lakhs
- Bimlesh Lochab, Funding Agency: DRDO
Project Title: Benzoxazine monomers and pre-polymers as Self-Healing Agents for Epoxy resins.
Duration: 2 years - 2014-2016
Budget amount: ₹ 9.9 Lakhs
- Goutam Chowdhury, Funding Agency: Department of Biotechnology Ramalingaswami Fellowship
Project Title: Role of 8-nitroguanosine and its analogs in chronic inflammation associated cancers.
2014 Budget amount: ₹ 32 Lakhs
All chemistry labs are equipped with fume-hoods, Schlenk lines, eyewash stations and safety showers. Synthetic lab facilities include LCMS-qToF, UV-visible and Infrared spectrophotometers, single crystal and powder XRD, flash chromatography, fluorimeter, glove box, bio-safety cabinets, CO2 Incubators, shaker incubators, flow cytometry, inverted microscope, plate reader, cell counter, fluorescent microscope, electroporator, PCR, RT-PCR, etc. Advanced analytical instrumentation such as 400 MHz NMR, HPLC, CHN analyzer, DSC, TGA, DLS, rheometer, SEM, AFM and Raman spectrometer are in the process of being acquired.
Computational facilities at SNS include a high performance IBM cluster (“Magus”) consisting of 32 compute nodes (plus two nodes with GPU processors) currently being expanded to 63 compute nodes (1008 cores) with a total capacity of 30 TF of Theoretical Peak Performance, plus 8 nodes with high-end CPUs. Additionally, several Linux workstations are used for teaching as well as research purposes. Software for bioinformatics and cheminformatics, molecular modeling, molecular dynamics, quantum chemistry, data analysis and statistical learning are also available.
Our library, housed in a modern 5-storey building, provides online access, from anywhere in the campus, to a large number of electronic journals and databases, including APS, AIP, ACS, RSC, AMS, SIAM, Springer, Elsevier, Wiley and Nature journals, in addition to various books, e-books and other learning resources.