Browsing by Author "Gyan Prakash Modi"

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Computational repurposing of potential dimerization inhibitors against sars-cov-2 main protease
(Bentham Science Publishers, 2024) Subhomoi Borkotoky; Archisha Prakash; Gyan Prakash Modi; Vikash Kumar Dubey
Background: The screening, design, and synthesis of various dimerization inhibitors have been an active area of interest for structure-based drug design efforts. Functionally important dimers, such as human immunodeficiency virus (HIV) protease and surviving, are being targeted for such studies over time. Computational repurposing of potential drug candidates provides a cost and time-efficient way in the drug discovery life cycle. Objective: Concerning the current coronavirus disease (COVID-19) scenario, the functionally active dimer of SARS-CoV-2 (severe acute respiratory syndrome) main protease (Mpro) is used as a target to screen possible dimerization inhibitors. Methods: A database of small molecule protein-protein interaction inhibitors was screened for the study. This study used molecular docking, followed by molecular dynamics (MD) simulation and postsimulation binding energy predictions. Results: From the selected 183 compounds, a diazene-based compound and a salicylic-type compound were identified as possible dimerization inhibitors in this study. These two compounds formed stable complexes with the Mpro during the MD simulations. The complexes formed by these two compounds were also unable to form important salt bridge interactions required for the dimerization of the protomers. Conclusion: Experimental studies on both compounds were previously conducted as dimerization inhibitors in HIV. The data led to the possibility of exploring the identified compounds as dimerization inhibitors, which could be important for SARS-CoV-2 therapeutics. © 2024 Bentham Science Publishers.
Design, synthesis and biological evaluation of novel piperic acid and benzylpiperazine hybrid molecules for improvement of memory impairment via cholinesterase inhibitory activity
(Springer Science and Business Media Deutschland GmbH, 2025) Jitendra Kumar; Gauri Shankar; S. Dasaratha Kumar; Gourav Singh; T. A. Gajendra; Sanskriti Rai; Upesh Mandloi; Saripella Srikrishna; Saroj Kumar; Amit Kumar Singh; Pradeep Harish Kumar; Kavindra Nath Tiwari; Sairam Krishnamurthy; Gyan Prakash Modi; Sunil Kumar Mishra
In this paper, we have developed a series of piperic acid (PA) derivatives to overcome the inherent constraints linked to PA for Alzheimer's disease (AD) management. We have carried out a comprehensive study to investigate the structure–activity relationship (SAR) of PAanalogs to enhance their inhibitory properties towards cholinesterase enzymes. Compound 3m exhibited notable inhibition against butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) among all developed analogs (BChE (µM), 1.03 ± 0.011; AChE (µM), 4.26 ± 0.13 respectively) over PA (AChE% inhibition at 20 µM, 7.14 ± 0.98; BChE% inhibition at 20 µM, 5.87 ± 0.76). Compound 3m was chosen for further biological investigations based on these encouraging outcomes. 3 m demonstrated a binding affinity for AChE’s peripheral anionic site, indicating its interaction with this specific enzyme region. Additionally, it also possesses favorable permeability across the blood–brain barrier, with a Pe (permeability coefficient) value of 5.79 ± 1.12. The molecular docking investigations unveiled the ability of 3mto intricately engage with AChE and BChE.In cell-based cytotoxicity tests, compound 3m displayed cell-friendly characteristics across different tested concentrations. Notably, 3m exhibited the ability to counteract scopolamine-induced memory impairmentin mice, enhancing both spatial and cognitive memories. These results strongly suggest that 3m can behave as a potential compound for AD management. © The Author(s), under exclusive licence to the Institute of Chemistry, Slovak Academy of Sciences 2024.
Discovery of novel hybrid tryptamine-rivastigmine molecules as potent AChE and BChE inhibitors exhibiting multifunctional properties for the management of Alzheimer's disease
(Elsevier Masson s.r.l., 2025) Gauri Shankar; Prabhat Kumar; Sanskriti Rai; Aparajita Ghosh; Tanmaykumar Varma; Mushtaq Ahmad Wani; Sunil N. Kumar; Upesh Mandloi; Gireesh Kumar Singh; Prabha Garg; Onkar Prakash Kulkarni; Saripella Srikrishna; Saroj Kumar; Gyan Prakash Modi
Contemporary research evidence has corroborated a gradual loss of central cholinergic neurons in Alzheimer's Disease (AD). This progressive deterioration leads to cognitive dysfunction and impaired motor activity, culminating in the brain cell's death in the disease. The approved drugs for AD treatment can only offer relief from symptoms without addressing the underlying pathological hallmarks of the disease. To address the limitations associated with rivastigmine (RIV), a marketed drug for AD, a series of tryptamine derivatives was designed, synthesized, and evaluated in various in-vitro and in-vivo AD models. Enzyme inhibition studies identified compounds 6d and 6e as the lead molecules with potent inhibitors against AChE (6d, IC50: 0.99 ± 0.009 nM and 6e IC50: 7.97 ± 0.016 nM and BChE (6d, IC50: 27.79 ± 0.21 nM and 6e, IC50: 0.79 ± 0.005 nM), compared to the marketed drug Riv (AChE, IC50: 6630 ± 0.76 nM, BChE IC50 = 91 ± 0.40 nM). The molecular docking and dynamics studies corroborated the enzyme inhibition studies. The PAMPA assay strongly suggested the BBB crossing ability of the lead molecules. Further, 6d and 6e demonstrated the capability to counteract oxidative stress and Aβ1-42 in various in-vitro studies. Compound 6e exhibited remarkable radical scavenging activity in the DPPH assay (IC50: 22.91 ± 1.73 μM) compared to rivastigmine (% radical scavenging activity: 3.71 ± 0.09 at 200 μM). Interestingly, 6d and 6e exhibited promising activity in the AD Drosophila model by protecting eye phenotypes from degeneration induced by Aβ1-42 toxicity and reduced mitochondrial and cellular oxidative stress in this model. Furthermore, upon oral administration, 6d and 6e could reverse scopolamine-induced amnesia by improving spatial and cognitive memory in mice at 0.3 and 0.5 mg/kg compared to rivastigmine at 3 mg/kg and were found to have potent ex-vivo anti-ChEs properties, which are correlated with the observed pro-cognitive effects in the Morris Water Maze, likely mediated through the inhibition of both cholinesterases. The expression of various neuroprotection markers, such as BDNF and TRKB, was significantly overexpressed compared to the disease control group. © 2024 Elsevier Masson SAS
New D-π-A-Based Coumarin- Derived Fluorescent Theranostic Probes With Broad-Spectrum Antimicrobial Activity
(John Wiley and Sons Inc, 2025) Himanshu Rai; Atul Kumar Tiwari; Aishwarya Nikhil; Ankit Tiwari; Prahalad Singh Bharti; Suresh Kumar Maury; Munesh Kumar Gupta; Sundaram Singh; Saroj Kumar; Gyan Prakash Modi
Understanding how multidrug-resistant (MDR) bacteria and fungi defy the existing antimicrobial agents requires innovative tools and techniques for real-time, in situ exploration of bacterial responses to antibiotics. Fluorescence-tagged antibiotics or dyes with inherent antimicrobial activity can provide a profound understanding of the molecular biology underlying antibiotic action and resistance mechanisms. Cutting-edge research highlights the pursuit of benzo-α-pyrone (coumarin) derivatives due to their excellent pharmacokinetics, diverse pharmacological activities, and innovative fluorescence molecular probes. In this study, donor-π-acceptor-based coumarin dyes were designed and evaluated for antimicrobial efficacy against fungal strains (Candida albicans), Gram-negative pathogens (Escherichia coli), and Gram-positive bacteria (Staphylococcus aureus). I-6 exhibited notable antimicrobial activity against S. aureus and C. albicans compared with E. coli. Conversely, I-9, a congener of I-6, showed a comparable affinity for S. aureus but found poor activity against the remaining tested strains. Mechanistic investigative studies unveiled that the inhibitory efficacy of I-6 can be attributed to its capacity to generate high reactive oxygen species (ROS) formation. Despite the evident antimicrobial potential of I-6 in the data, our future prospects, including real-time visualization to study physiological processes like uptake, distribution, and mechanism of action through fluorescence-based imaging modalities, could enhance the applicability of these probes. © 2025 Deutsche Pharmazeutische Gesellschaft.