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Projects

				
					2020-2023
Selective Pharmacological Inhibition of the Transcriptional Anti-terminator Protein, RfaH of Klebsiella pneumoniae
Funded by the Department of Health Research
Ministry of Health, Government of India
(₹64.78 L)
				
			
				
					2020-2023
Structure-based Design and Development of Selective Sphingosine Kinase 1 Inhibitors to Combat Idiopathic Pulmonary Fibrosis
Funded by the Indian Council of Medical Research
Ministry of Health, Government of India
(₹36.45 L)
				
			
				
					2020-2023
Identification of MARK 4 inhibitors from bioactive phytoconstituents of Bacopa Monnieri (Brahmi): Therapeutic management of Alzheimer’s disease and neuro-inflammation animal model
Funded by the National Medicinal Plant Board
Ministry of AYUSH, Government of India
(₹22.20 L)
				
			
				
					2020-2023
Elucidation of neurodegenerative tauopathies through MARK4 inhibitors: Design and evaluation of MARK4 inhibitors using in silico and in vitro approaches and investigation of their role to cure hyper phosphorylation of tau proteins
Funded by the Indian Council of Medical Research
Ministry of Health, Government of India
(₹56.39 L)
				
			
				
					2020-2023
Identification of a high affinity selective inhibitor of calcium/calmodulin-dependent protein kinase IV by a combined experimental and computational approach 
Funded by the Indian Council of Medical Research
Ministry of Health, Government of India
(₹52.70 L)
				
			
				
					2020-2023
In Silico (Molecular Dynamic Simulation) and In Vitro Approaches to Understand Counteraction of Urea’s Effects on Proteins by Kidney Osmolytes (Co-PI) 
Funded by the Indian Council of Medical Research
Ministry of Health, Government of India
(₹46.39 L)
				
			
				
					2020-2023
Systems Regulatory Networks of Autophagy Proteins in Leishmania: Implications towards Drug Design (Co-PI)
Funded by the Indian Council of Medical Research
Ministry of Health, Government of India
(₹34.39 L)
				
			
				
					2020-2023
Targeting Alzheimer disease by a mixture of Unani plant extract via modulation of human kinase 
Funded by the Central Council for Research in Unani Medicine
Ministry of AYUSH, Government of India
(₹22.10 L)
				
			
				
					2020-2023
Developing small molecule inhibitors to target non-genomic androgen signaling and elucidating the role of GPR56 in Prostate Cancer (Co-PI)
Funded by the Department of Science and Technology
Ministry of Science and Technology, Government of India
(₹43.10 L)
				
			
				
					2020-2023
Development of Pim-1 Kinase-Specific Inhibitors as Preclinical Lead for the Prostate Cancer Therapy  
Funded by the Council of Scientific & Industrial Research
Government of India
(₹42.60 L)
				
			
				
					2020-2023
Design & development of SARS-CoV-2 main Protease Inhibitors
Funded by ISTI-CP China
Projects Completed
Design and development of potent and selective inhibitors of MARK4

​Microtubule affinity-regulating kinase 4 (MARK4) is a potential drug target and is found to be associated with the development of neurodegenerative disease, diabetes, and varying types of cancer. We have synthesized and characterized Isatin-triazole hydrazones and developed a compound bearing excellent binding affinity and consequential enzyme inhibition potential in the submicromolar range. The same compounds possess excellent inhibition of cell proliferation and cell migration in MCF-7, MDA-MB-435s, and HepG2 cells with significantly very high IC50 values. During the analysis of mechanism we found that this compound causes oxidative stress resulting in apoptosis and showing a remarkable MARK4 specific selectivity profile. Similarly, some acridone derivatives were synthesized, characterized, and evaluated for inhibitory activity against human MARK4 and showing excellent drug-like features the same as we found in hydrazones. Using the chemical hybridization approach, we have synthesized 3-N-aryl substituted-2-heteroarylchromones which shows excellent binding affinity and specificity with the MARK4. The same compound inhibited the cell viability, induced apoptosis, and lowered the tau-phosphorylation in cancer cells. In addition, we have discovered a series of compounds which bearing remarkable inhibitory potential to MARK4 and inhibits cancer cell growth via apoptosis.

  1. Voura M, Khan P, Thysiadis S, Katsamakas S, Queen A, Hasan GM, Sarli V, Hassan MI.  (2019) Probing the Inhibition of Microtubule Affinity Regulating Kinase 4 by a Novel Class of N-Substituted Acridone Derivatives: Synthesis, Characterization and Biological Evaluation. Scientific Reports 9(1):1676.

  2. Aneja B, Khan NS, Khan P, Queen A, Hussain A, Rehman MT, Alajmie MF, El-Seedif HR, Ali S, Hassan MI, Abid M, (2019) Design and development of Isatin-triazole hydrazones as potential inhibitors of microtubule affinity-regulating kinase 4 for the therapeutic management of cell proliferation and metastasis. Eur J Med Chem 163:840-852.

  3. Parveen I, Khan P, Alis S, Hassan MI and Ahmad N (2018) Synthesis, Molecular docking and Inhibition studies of novel 3-N-aryl substituted-2-heteroarylchromones targeting Microtubule Affinity Regulating Kinase 4 Inhibitors.  European Journal of Medicinal Chemistry 59:166-177.

  4. Shamsi, A.; Anwar, S.; Mohammad, T.; Alajmi, M.F.; Hussain, A.; Rehman, M.T.; Hasan, G.M.; Islam, A.; Hassan, M.I. MARK4 Inhibited by AChE Inhibitors, Donepezil and Rivastigmine Tartrate: Insights into Alzheimer’s Disease Therapy. Biomolecules 2020, 10, 789.

  5. Anwar S, Shamsi A, Shahbaaz M, Queen A, Khan P, Hasan GM, Islam A, Alajmi MF, Hussain A, Ahmad F, Hassan MI (2020) Rosmarinic Acid Exhibits Anticancer Effects via MARK4 Inhibition. Scientific Reports (In Press).

  6. Khan NS, Khan P, Inam A, Ahmad K, Yousuf M, Islam A, Ali S, Azam A, Husain M, and Hassan MI (2020) Discovery of 4-(2-(dimethylamino) ethoxy) benzo-hydrazide derivatives as prospective microtubule affinity regulating kinase 4 inhibitors. RSC Advances (In Press).

As we know that India remains the source of knowledge and national therapy from ancient time. However, the mechanism of action verities of natural compounds is remaining elusive. We have exploited a series of natural compounds that are known to possess anticancer properties and dissected their mechanism of action using cutting-edge computational, molecular, and cellular biology-based methods. We found that α-mangostin is showing the excellent binding affinity and inhibited MARK4 activity with an IC50 value of 1.47 μM and binding constant (Ka) 5.2 × 107 M-1 and induces apoptosis, arrested the cell cycle in the G0/G1 phase, and reduced tau-phosphorylation. We have also identified many phytochemicals that significantly inhibit the kinase activity of MARK4, CAMKIV, FASTK, PDK3, ILK, and SPhK1. Using high throughput screening methods coupled with chemical synthesis, we have developed many potent and selective MARK4 inhibitors. These designed inhibitors show strong binding affinity and subsequently inhibit kinase activity with the IC50 value in the nM range. Our designed inhibitors showed inhibition of cell proliferation and migration. In addition, these compounds induce apoptosis, cause oxidative stress resulting in apoptosis. The newer drug-like molecules discovered in our lab are acting upon the newer targets impeding the process of cancer cell proliferation are no longer a mere dream, instead, this has now become a reality.

  1. Khan P, Queen A, Mohammad T, Smita NA, Nashrah NS, Zubair H, Hassan MI, Ali S (2019) Identification of α-Mangostin as a Potential Inhibitor of Microtubule Affinity Regulating Kinase 4. Journal of Natural Products 82(8):2252-2261.

  2. Khan P, Manzoor S, Queen A, Naz F. Rahman S, Kim J, Luqman S, Hasan GM, Islam A, Ahmad F and Hassan MI (2017) Elucidation of Dietary Polyphenolics as Potential Inhibitor of Microtubule Affinity Regulating Kinase 4: In silico and In vitro Studies. Scientific Reports   7(1):9470.

  3. Khan NS, Khan P, Ansari MF, Srivastava S, Hasan GM, Husain M, Hassan MI. (2018) Thienopyrimidine-Chalcones Hybrid Molecules Inhibits Fas-activated Serine/Threonine Kinase: An Approach to Ameliorates Antiproliferation in Human Breast Cancer Cells. Molecular Pharmaceutics 15(9):4173-4189.

  4. Gupta P, Mohammad T, Khan P, Roy S, Alajmi F, Hussain A, Hassan MI (2019) Evaluation of Ellagic Acid as an Inhibitor of Sphingosine Kinase 1: A Targeted Approach towards Anticancer Therapy. Biomedicine & Pharmacotherapy 118:109245.

  5. Anwar, S.; Mohammad, T.; Shamsi, A.; Queen, A.; Parveen, S.; Luqman, S.; Hasan, G.M.; Alamry, K.A.; Azum, N.; Asiri, A.M.; Hassan, M.I. (2020) Discovery of Hordenine as a Potential Inhibitor of Pyruvate Dehydrogenase Kinase 3: Implication in Lung Cancer Therapy. Biomedicines, 8(5): E119.

  6. Yousuf M, Shamsi A, Khan P, Shahbaaz M, AlAjmi MF, Hussain A, Hasan GM, Islam A, Haque QMR and Hassan MI (2020) Ellagic Acid Controls Cell Proliferation and Induces Apoptosis in Breast Cancer Cells via inhibition of Cyclin-Dependent Kinase 6.  International Journal of Molecular Sciences 21(10): E3526.

  7. Dahiya R, Mohammad T, Khan P, Roy S, Anwar S, Gupta P, Alajmi F, Hussain A, Hassan MI (2019) Molecular interaction studies on ellagic acid for its anticancer potential targeting pyruvate dehydrogenase kinase 3. RSC Advances 9, 23302-23315.

As we know that India remains the source of knowledge and national therapy from ancient time. However, the mechanism of action verities of natural compounds is remaining elusive. We have exploited a series of natural compounds that are known to possess anticancer properties and dissected their mechanism of action using cutting-edge computational, molecular, and cellular biology-based methods. We found that α-mangostin is showing the excellent binding affinity and inhibited MARK4 activity with an IC50 value of 1.47 μM and binding constant (Ka) 5.2 × 107 M-1 and induces apoptosis, arrested the cell cycle in the G0/G1 phase, and reduced tau-phosphorylation. We have also identified many phytochemicals that significantly inhibit the kinase activity of MARK4, CAMKIV, FASTK, PDK3, ILK, and SPhK1. Using high throughput screening methods coupled with chemical synthesis, we have developed many potent and selective MARK4 inhibitors. These designed inhibitors show strong binding affinity and subsequently inhibit kinase activity with the IC50 value in the nM range. Our designed inhibitors showed inhibition of cell proliferation and migration. In addition, these compounds induce apoptosis, cause oxidative stress resulting in apoptosis. The newer drug-like molecules discovered in our lab are acting upon the newer targets impeding the process of cancer cell proliferation are no longer a mere dream, instead, this has now become a reality.

  1. Khan P, Queen A, Mohammad T, Smita NA, Nashrah NS, Zubair H, Hassan MI, Ali S (2019) Identification of α-Mangostin as a Potential Inhibitor of Microtubule Affinity Regulating Kinase 4. Journal of Natural Products 82(8):2252-2261.

  2. Khan P, Manzoor S, Queen A, Naz F. Rahman S, Kim J, Luqman S, Hasan GM, Islam A, Ahmad F and Hassan MI (2017) Elucidation of Dietary Polyphenolics as Potential Inhibitor of Microtubule Affinity Regulating Kinase 4: In silico and In vitro Studies. Scientific Reports   7(1):9470.

  3. Khan NS, Khan P, Ansari MF, Srivastava S, Hasan GM, Husain M, Hassan MI. (2018) Thienopyrimidine-Chalcones Hybrid Molecules Inhibits Fas-activated Serine/Threonine Kinase: An Approach to Ameliorates Antiproliferation in Human Breast Cancer Cells. Molecular Pharmaceutics 15(9):4173-4189.

  4. Gupta P, Mohammad T, Khan P, Roy S, Alajmi F, Hussain A, Hassan MI (2019) Evaluation of Ellagic Acid as an Inhibitor of Sphingosine Kinase 1: A Targeted Approach towards Anticancer Therapy. Biomedicine & Pharmacotherapy 118:109245.

  5. Anwar, S.; Mohammad, T.; Shamsi, A.; Queen, A.; Parveen, S.; Luqman, S.; Hasan, G.M.; Alamry, K.A.; Azum, N.; Asiri, A.M.; Hassan, M.I. (2020) Discovery of Hordenine as a Potential Inhibitor of Pyruvate Dehydrogenase Kinase 3: Implication in Lung Cancer Therapy. Biomedicines, 8(5): E119.

  6. Yousuf M, Shamsi A, Khan P, Shahbaaz M, AlAjmi MF, Hussain A, Hasan GM, Islam A, Haque QMR and Hassan MI (2020) Ellagic Acid Controls Cell Proliferation and Induces Apoptosis in Breast Cancer Cells via inhibition of Cyclin-Dependent Kinase 6.  International Journal of Molecular Sciences 21(10): E3526.

  7. Dahiya R, Mohammad T, Khan P, Roy S, Anwar S, Gupta P, Alajmi F, Hussain A, Hassan MI (2019) Molecular interaction studies on ellagic acid for its anticancer potential targeting pyruvate dehydrogenase kinase 3. RSC Advances 9, 23302-23315.

Protein aggregation and misfolding is directly associated with the neurodegenerative diseases. We have established the underlying mechanism of amyotrophic lateral sclerosis (ALS) by dissecting the folding pathways of associated proteins. ALS and frontotemporal dementia (FTD) are related neurodegenerative disorders which are characterized by a rapid decline in cognitive and motor functions, and short survival. We found that stability of the ALS mutants correlated well with the duration of disease progression as compared to FTD-ALS mutants. This comprehensive analysis provides the understanding of the mechanism of ALS. TDP-43 is largely involved in the ALS and frontotemporal dementia (FTD). Structural regions mediating the formation of cytoplasmic pathological aggregates in TDP-43 is still unknown. Recently, we have identified three aggregation-prone peptides and validated their aggregation potential through biophysical techniques and MD simulation which would help in designing peptide-based inhibitors of TDP-43 aggregation for therapeutic. The structural rearrangements of RRM2 could lead to aberrant protein-protein interactions that may account for enhanced aggregation and toxicity of TDP-43. Cu, Zn Superoxide Dismutase (SOD1) has also been reported to be associated with the progression of ALS because of its misfolding. We reported that the formation of aggregation by local unfolding of apo monomer is the main cause of SOD1 fibrillar aggregation and found an altered protein conformation and dynamics within its structure may underlie the aggregation of SOD1 in ALS. We have further reported that TFE induces partially unfolded β-sheet-rich extended conformations in these SOD1 variants, which subsequently develops aggregates with fibril-like characteristics. Fibrillation was achieved more easily in disulfide-reduced monomeric SOD1 when compared with wild-type and mutant monomeric SOD1. We also analyzed patient’s data in relation to experimental and computed protein stabilities for mutations of human SOD1. Correlation between disease phenotypes and stability changes suggest that the changes in SOD1 stability correlate with ALS patient survival times. In addition, we have reported the role of RNA-mediated toxicity of C9orf72 repeats in C9-FTD/ALS.

  1. Kumar V, Prakash A, Pandey P, Lynn AM, Hassan MI (2018) TFE-induced local unfolding and fibrillation of SOD1: bridging the experiment and simulation studies. Biochemical Journal 475(10):1701-1719.

  2. Kumar V, Islam A, Hassan MI, Ahmad F (2016) Delineating the relationship between amyotrophic lateral sclerosis and frontotemporal dementia: Sequence and Structure-based predictions. BBA – Molecular Basis of Disease 1862(9):1742-1754.

  3. Sami N, Kumar V, Ali, S, Islam A, Ahmad F, Hassan MI. (2017) Exploring Missense Mutations in Tyrosine Kinases Implicated with Neurodegeneration. Molecular Neurobiology 54(7):5085-5106.

  4. Kumar V, Rahman S, Choudhry H, Zamzami MA, Sarwar Jamal M, Islam A, Ahmad F, Hassan MI (2017) Computing disease-linked SOD1 mutations: deciphering protein stability and patient-phenotype relations. Scientific Reports 7(1):4678.

  5. Kumar V, Wahiduzzaman, Prakash A, Tomar AK, Srivastava A, Kundu B, Lynn AM, Hassan MI (2019) Exploring the aggregation-prone regions from structural domains of human TDP-43. Biochim Biophys Acta Proteins Proteomics 1867(3):286-296.

  6. Husain S, Kumar V, Hassan MI. (2018) Phosphorylation-induced changes in the energetic frustration in human Tank binding kinase 1. Journal of Theoretical Biology 449:14-22.

  7. Kumar V, Hasan GM and Hassan MI (2017) Unraveling the Role of RNA Mediated Toxicity of C9orf72 Repeats in C9-FTD/ALS. Frontiers in Neuroscience 11:711.

  8. Sami N, Rahman S, Kumar V, Zaidi S, Islam A, Ali S, Ahmad F, Hassan MI. (2017) Protein aggregation, misfolding and consequential human neurodegenerative diseases.  International Journal of Neuroscience 127(11):1047-1057.

  9. Prakash A, Kumar V, Meena NK, Hassan MI, Lynn AM (2019) Comparative analysis of thermal unfolding simulations of RNA recognition motifs (RRMs) of TAR DNA-binding protein 43 (TDP-43). Journal of Biomolecular Structure & Dynamics 37(1):178-194.

  10. Prakash A, Kumar V, Pandey P, Bharti DR, Vishwakarma P, Singh R, Hassan MI, Lynn AM (2018) Solvent sensitivity of protein aggregation in Cu, Zn superoxide dismutase: A molecular dynamics simulation study. Journal of Biomolecular Structure and Dynamics 36(10):2605-2617.

Telomere comprises the ends of eukaryotic linear chromosomes and is composed of G-rich (TTAGGG) tandem repeats which play an important role in maintaining genome stability, premature aging and onsets of many diseases. Majority of the telomere are replicated by conventional DNA replication, and only the last bit of the lagging strand is synthesized by telomerase (a reverse transcriptase). In addition to replication, telomere maintenance is principally carried out by two key complexes known as shelterin (TRF1, TRF2, TIN2, RAP1, POT1, and TPP1) and CST (CDC13/CTC1, STN1, and TEN1). Shelterin protects the telomere from DNA damage response (DDR) and regulates telomere length by telomerase; while, CST govern the extension of telomere by telomerase and C strand fill-in synthesis. We have investigated both structural and biochemical features of shelterin and CST complexes to get a clear understanding of their importance in the telomere maintenance. Further, we have analyzed ~115 clinically important mutations in both of the complexes. Association of such mutations with specific cellular fault unveils the importance of shelterin and CST complexes in the maintenance of genome stability. A possibility of targeting shelterin and CST by small molecule inhibitors is further investigated towards the therapeutic management of associated diseases. Overall, this review provides a possible direction to understand the mechanisms of telomere borne diseases, and their therapeutic intervention.

  1. Amir M, Mohammad T, Dohare R, Islam A, Ahmad F and Hassan MI (2020) Structure, function and therapeutic implications of OB-fold proteins: A lesson from past to present. Briefings in Functional Genomics, elaa008.

  2. Amir, M.; Khan, P.; Queen, A.; Dohare, R.; Alajmi, M.F.; Hussain, A.; Islam, A.; Ahmad, F.; Hassan, I. Structural Features of Nucleoprotein CST/Shelterin Complex Involved in the Telomere Maintenance and Its Association with Disease Mutations. Cells 2020, 9, 359.

  3. Amir, M., Mohammad, T., Kumar, V., Alajmi, M.F., Rehman, M.T., Hussain, A., Alam, P., Dohare, R., Islam, A., Ahmad, F. and Hassan MI (2019). Structural Analysis and Conformational Dynamics of STN1 Gene Mutations Involved in Coat Plus Syndrome. Frontiers in Molecular Biosciences 6, 41.

  4. Amir M, Kumar V, Dohare R, Rehman MT, Hussain A, Alajmi MF, Hassan HMA, Islam A, Ahmad F, Hassan MI. (2019) Investigating architecture and structure-function relationships in cold shock DNA-binding domain family using structural genomics-based approach. International Journal of Biological Macromolecules 133:484-494.

  5. Amir M, Kumar V, Dohare R, Hussain A, Rehman MT, Alajami MF, Islam A, Ahmad F, Hassan MI. (2019) Structural and functional impact of non-synonymous SNPs in the CST complex subunit TEN1: Structural genomics approach. Bioscience Reports 39(5): BSR20190312.

  6. Amir M, Kumar V, Dohare R, Hussain A, Rehman MT, Alajami MF, Islam A, Ahmad F, Hassan MI. (2019) Investigation of deleterious effects of nsSNPs in POT1 gene: A structural genomics-based approach to understand mechanism of cancer development. Journal of Cellular Biochemistry 120(6):10281-10294.

About

We are a drug discovery lab working on targeting human kinases. We works on the determination of three-dimensional structure of human kinases and their complexes with potential inhibitors Read More..

Contact

G-20, Srinivasan Ramanujan Block, Mujeeb Bagh, Jamia Nagar, New Delhi – 110025, INDIA
Tel.: +91-11-26983409 Mob: +91 9756014962 (Taj
[email protected]

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