Browsing by Author "Ankur Kumar"

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A novel inhibitor L755507 efficiently blocks c-Myc–MAX heterodimerization and induces apoptosis in cancer cells
(American Society for Biochemistry and Molecular Biology Inc., 2021) Ashutosh Singh; Ankur Kumar; Prateek Kumar; Namyashree Nayak; Taniya Bhardwaj; Rajanish Giri; Neha Garg
c-Myc is a transcription factor that plays a crucial role in cellular homeostasis, and its deregulation is associated with highly aggressive and chemotherapy-resistant cancers. After binding with partner MAX, the c-Myc–MAX heterodimer regulates the expression of several genes, leading to an oncogenic phenotype. Although considered a crucial therapeutic target, no clinically approved c-Myc-targeted therapy has yet been discovered. Here, we report the discovery via computer-aided drug discovery of a small molecule, L755507, which functions as a c-Myc inhibitor to efficiently restrict the growth of diverse Myc-expressing cells with low micromolar IC50 values. L755507 successfully disrupts the c-Myc–MAX heterodimer, resulting in decreased expression of c-Myc target genes. Spectroscopic and computational experiments demonstrated that L755507 binds to the c-Myc peptide and thereby stabilizes the helix–loop–helix conformation of the c-Myc transcription factor. Taken together, this study suggests that L755507 effectively inhibits the c-Myc–MAX heterodimerization and may be used for further optimization to develop a c-Myc-targeted antineoplastic drug. © 2021 THE AUTHORS.
Amyloidogenic proteins in the SARS-CoV and SARS-CoV-2 proteomes
(Nature Research, 2023) Taniya Bhardwaj; Kundlik Gadhave; Shivani K. Kapuganti; Prateek Kumar; Zacharias Faidon Brotzakis; Kumar Udit Saumya; Namyashree Nayak; Ankur Kumar; Richa Joshi; Bodhidipra Mukherjee; Aparna Bhardwaj; Krishan Gopal Thakur; Neha Garg; Michele Vendruscolo; Rajanish Giri
The phenomenon of protein aggregation is associated with a wide range of human diseases. Our knowledge of the aggregation behaviour of viral proteins, however, is still rather limited. Here, we investigated this behaviour in the SARS-CoV and SARS-CoV-2 proteomes. An initial analysis using a panel of sequence-based predictors suggested the presence of multiple aggregation-prone regions (APRs) in these proteomes and revealed a strong aggregation propensity in some SARS-CoV-2 proteins. We then studied the in vitro aggregation of predicted aggregation-prone SARS-CoV and SARS-CoV-2 proteins and protein regions, including the signal sequence peptide and fusion peptides 1 and 2 of the spike protein, a peptide from the NSP6 protein, and the ORF10 and NSP11 proteins. Our results show that these peptides and proteins can form amyloid aggregates. We used circular dichroism spectroscopy to reveal the presence of β-sheet rich cores in aggregates and X-ray diffraction and Raman spectroscopy to confirm the formation of amyloid structures. Furthermore, we demonstrated that SARS-CoV-2 NSP11 aggregates are toxic to mammalian cell cultures. These results motivate further studies about the possible role of aggregation of SARS proteins in protein misfolding diseases and other human conditions. © 2023, The Author(s).
Conformational dynamics of 13 amino acids long NSP11 of SARS-CoV-2 under membrane mimetics and different solvent conditions
(Academic Press, 2021) Kundlik Gadhave; Prateek Kumar; Ankur Kumar; Taniya Bhardwaj; Neha Garg; Rajanish Giri
The intrinsically disordered proteins/regions (IDPs/IDPRs) are known to be responsible for multiple cellular processes and are associated with many chronic diseases. In viruses, the existence of a disordered proteome is also proven and is related to its conformational dynamics inside the host. The SARS-CoV-2 has a large proteome, in which, structure and functions of all proteins are not known yet, along with non-structural protein 11 (nsp11). In this study, we have performed extensive experimentation on nsp11. Our results based on the CD spectroscopy gives characteristic disordered spectrum for IDPs. Further, we investigated the conformational behavior of nsp11 in the presence of membrane mimetic environment, α-helix inducer, and natural osmolyte. In the presence of negatively charged and neutral liposomes, nsp11 remains disordered. However, with SDS micelle, it adopted an α-helical conformation, suggesting the helical propensity of nsp11. Finally, we again confirmed the IDP behavior of nsp11 using MD simulations. In future, this conformational dynamic study could help to clarify its functional importance in SARS-CoV-2 infection. © 2021 Elsevier Ltd
Experimental investigation of acoustically forced helium jet in crossflow using shadowgraphy and modal analysis
(American Institute of Physics, 2025) Ankur Kumar; Sita Ram Sahu; Narsing Kumar Jha; Anubhav Sinha
This study presents an experimental investigation of helium jet in a crossflow of air, with an objective to understand the influence of acoustic forcing on jet behavior and mixing. Unforced and sinusoidally forced jets are studied. High-speed shadowgraphy is used to capture instantaneous jet images. These images are further processed using the Proper Orthogonal Decomposition (POD) algorithm to provide insights into the spatiotemporal behavior. Schlieren Imaging Velocimetry (SIV) is also used to understand jet entrainment and identify regions of low and high velocities. Moreover, an interface tracking method is used to obtain interface location oscillations for near nozzle and far field locations. The energy spectrum of these oscillations is obtained through a Fast Fourier Transform (FFT) analysis. The unforced jet is observed for different jet-to-crossflow velocity ratios (R), and it is observed that the jet penetration increases with R. Unforced cases show a broadband spectrum, indicating the absence of any dominant frequency, except for the lowest velocity ratio case. The instability in unforced cases is limited to shear layer oscillations. For the forced cases, a clear dominant frequency corresponding to the forcing frequency (and occasionally their harmonics) is recorded. It is observed that the impact of forcing function is not the same for all the frequencies, and the jet response is observed to be much more pronounced for a higher frequency as compared to a lower frequency forcing. Two typical cases, highlighting the effect of frequency response, are compared in detail using image analysis, interface tracking, POD, and SIV. © 2025 Author(s).
One microsecond MD simulations of the SARS-CoV-2 main protease and hydroxychloroquine complex reveal the intricate nature of binding
(Taylor and Francis Ltd., 2022) Prateek Kumar; Taniya Bhardwaj; Ankur Kumar; Neha Garg; Rajanish Giri
Currently, several vaccines and antivirals across the globe are in clinical trials. Hydroxychloroquine (HCQ) was reported to inhibit the SARS-CoV-2 virus in antiviral assays. Here, it raises the curiosity about the molecular target of HCQ inside the cell. It may inhibit some of the viral targets, or some other complex mechanisms must be at disposal towards action mechanisms. In some of the viruses, proteases are experimentally reported to be a potential target of HCQ. However, no in-depth investigations are available in the literature yet. Henceforth, we have carried out extensive, one-microsecond long molecular dynamics simulations of the bound complex of hydroxychloroquine with main protease (Mpro) of SARS-CoV-2. Our analysis found that HCQ binds within the catalytic pocket of Mpro and remains stable upto one-third of simulation time but further causes increased fluctuations in simulation parameters. In the end, the HCQ does not possess any pre-formed hydrogen bond, other non-covalent interactions with Mpro, ultimately showing the unsteadiness in binding at catalytic binding pocket and may suggest that HCQ may not inhibit the Mpro. In the future, this study would require experimental validation on enzyme assays against Mpro, and that may be the final say. Communicated by Ramaswamy H. Sarma. © 2021 Informa UK Limited, trading as Taylor & Francis Group.
Reprofiling of approved drugs against SARS-CoV-2 main protease: an in-silico study
(Taylor and Francis Ltd., 2022) Prateek Kumar; Taniya Bhardwaj; Ankur Kumar; Bhuvaneshwari R. Gehi; Shivani K. Kapuganti; Neha Garg; Gopal Nath; Rajanish Giri
Given the COVID-19 pandemic, currently, there are many drugs in clinical trials against this virus. Among the excellent drug targets of SARS-CoV-2 are its proteases (Nsp3 and Nsp5) that plays vital role in polyprotein processing giving rise to functional nonstructural proteins, essential for viral replication and survival. Nsp5 (also known as Mpro) hydrolyzes replicase polyprotein (1ab) at eleven different sites. For targeting Mpro, we have employed drug repurposing approach to identify potential inhibitors of SARS-CoV-2 in a shorter time span. Screening of approved drugs through docking reveals Hyaluronic acid and Acarbose among the top hits which are showing strong interactions with catalytic site residues of Mpro. We have also performed docking of drugs Lopinavir, Ribavirin, and Azithromycin on SARS-CoV-2 Mpro. Further, binding of these compounds (Hyaluronic acid, Acarbose, and Lopinavir) is validated by extensive molecular dynamics simulation of 500 ns where these drugs show stable binding with Mpro. We believe that the high-affinity binding of these compounds will help in designing novel strategies for structure-based drug discovery against SARS-CoV-2. Communicated by Ramaswamy H. Sarma. © 2020 Informa UK Limited, trading as Taylor & Francis Group.
Salvianolic acid B noncovalently interacts with disordered c-Myc: A computational and spectroscopic-based study
(Future Medicine Ltd., 2021) Ashutosh Singh; Ankur Kumar; Prateek Kumar; Taniya Bhardwaj; Rajanish Giri; Neha Garg
Aims: c-Myc, along with its partner MAX, regulates the expression of several genes, leading to an oncogenic phenotype. The MAX interacting interface of c-Myc is disordered and uncharacterized for small molecule binding. Salvianolic acid B possesses numerous therapeutic properties, including anticancer activity. The current study was designed to elucidate the interaction of the Sal_Ac_B with the disordered bHLH domain of c-Myc using computational and biophysical techniques. Materials & methods: The binding of Sal_Ac_B with Myc was studied using computational and biophysical techniques, including molecular docking and simulation, fluorescence lifetime, circular dichroism and anisotropy. Results & conclusions: The study demonstrated a high binding potential of Sal_Ac_B against the disordered Myc peptide. The binding of the compounds leads to an overall conformational change in Myc. Moreover, an extensive simulation study showed a stable Sal_Ac_B/Myc binding. © 2021 Future Medicine Ltd.. All rights reserved.
The multi-protein targeting potential of bioactive syringin in inflammatory diseases: using molecular modelling and in-silico analysis of regulatory elements
(Taylor and Francis Ltd., 2024) Vipendra Kumar Singh; D.C. Thakur; Naina Rajak; Anand Mishra; Ankur Kumar; Rajanish Giri; Neha Garg
Inflammation plays a crucial role in the onset or progression of a variety of acute and chronic diseases. Non-steroidal anti-inflammatory drugs (NSAIDs) are the only available FDA-approved therapy. The therapeutic outcome of NSAIDs is still finite due to off-target effects and extreme side effects on other vital organs. Bioactive syringin has been manifested to hold anti-osteoporosis, cardiac hypertrophy, alter autophagy, anti-cancer, neuro-preventive effects, etc. However, its multi-protein targeting potential in inflammation mostly remains unexplored. In the present work, we have checked the multi-protein targeting potential of bioactive glycoside syringin in inflammatory diseases. Based on the binding score of protein-ligand complexes, glycoside syringin scored greater than −7 kcal/mol against 12 inflammatory proteins. Our molecular dynamic simulation study (200 ns) confirmed that bioactive syringin remained inside the binding cavity of inflammatory proteins (JAK1, TYK2, and COX1) in a stable conformation. Further, our co-expression analysis suggests that these genes play an essential role in multiple pathways and are regulated by multiple miRNAs. Our study demonstrates that bioactive glycoside syringin might be a multi-protein targeting potential against inflammatory diseases and could be further investigated utilizing different preclinical approaches. Communicated by Ramaswamy H. Sarma. © 2023 Informa UK Limited, trading as Taylor & Francis Group.
Therapeutic potential of genome editing tools in neurodegenerative diseases
(Elsevier, 2024) Ankur Kumar; Nandigam Pardhipa; Sachin G. Swami; Vibha Dwivedi; Anand K. Singh
Progressive functional impairment of certain populations of neurons is a hallmark of neurodegenerative diseases (NDs) like Parkinson’s disease, Alzheimer’s disease, frontotemporal dementia, tauopathies, and amyotrophic lateral sclerosis. The most prominent cytological feature of degenerating neurons is pathogenic aggregates of misfolded proteins in the cytoplasm, which hamper the proper development and functioning of neuronal cells. Different approaches have been implemented to study the mechanism of pathogenesis and explore the therapeutics of different NDs. Genome editing tools are the most powerful and widely used approach to studying NDs by inducing desired modifications at the targeted genome site, offering a more promising approach to treatment than conventional techniques. This chapter covers the recent developments in the three main genome editing techniques, including transcription activator-like effector nucleases (TALENs), zinc-finger nucleases (ZFNs), and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9). Despite the potential benefits of these editing tools, challenges like selecting the most suitable delivery techniques, safety issues, off-target impacts, and enhanced mosaicism must be addressed to maximize their potential in treating NDs. © 2025 Elsevier Inc. All rights are reserved including those for text and data mining AI training and similar technologies.