Browsing by Author "Ravi Saini"

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Discovery of platelet glycoprotein VI receptor antagonists and their neuroprotective activity: an in silico, in vitro, and in vivo study
(Springer Science and Business Media Deutschland GmbH, 2025) Mohammad Aquib Siddiqui; Poorvi Saraf; Sushant Kumar Shrivastava; Sudha Madhavi Penumaka; Debabrata Mandal; Ravi Saini; Abhishek Pathak; Ramakrishna Kakarla; Sairam Krishnamurthy
The present study utilized a drug repurposing approach to identify potential GPVI receptor antagonists among FDA-approved drugs. Computational and molecular dynamics simulations revealed that adapalene and ranolazine exhibit strong binding affinities to GPVI receptors and stabilize GPVI proteins, respectively. Both compounds inhibited collagen-induced platelet aggregation, evidenced by the suppression of Syk tyrosine kinase expression, a marker of platelet activation, via GPVI stimulation, as confirmed through flow cytometry analysis. Further analysis using circular dichroism and Raman spectroscopy indicated that collagen exposure induced conformational changes in the α-helical domains of platelets, which were stabilized upon treatment with adapalene and ranolazine. Moreover, thrombotic events can lead to cerebral cell death due to hypoxia, which may be mitigated by neuroprotective compounds. Adapalene and ranolazine were assessed for their neuroprotective capabilities. The results showed that these compounds exhibited neuroprotective effects in SHSY5Y neuroblastoma cells subjected to oxygen–glucose deprivation/reperfusion (OGD/R) injury, reducing HIF-1α expression, ROS production, lipid peroxidation, and caspase-3 levels, while also improving mitochondrial membrane potential and glutathione levels. Acridine orange and propidium iodide staining studies further confirmed a decrease in apoptosis. In the FeCl3-induced carotid artery thrombosis model, ranolazine effectively inhibited platelet aggregation by modulating GPVI receptor activity, reducing intracellular calcium levels, and enhancing cAMP signaling. It also suppressed critical platelet activation mediators, including COX-1, TXB2, and PGE2, thereby mitigating thrombus formation. Collectively, these results suggest that adapalene and ranolazine may serve as multimodal therapeutic agents with the potential to treat both thrombotic and neurological diseases. Future studies focusing on the adapalene and ranolazine molecular mechanisms, bleeding risk, dose titration, and long-term safety while managing thrombotic disorders have to be investigated. © King Abdulaziz City for Science and Technology 2025.
Discovery of the allosteric inhibitor from actinomyces metabolites to target EGFRCSTMLR mutant protein: molecular modeling and free energy approach
(Nature Research, 2023) Ravi Saini; Sonali Kumari; Aditi Bhatnagar; Amit Singh; Abha Mishra
EGFR (epidermal growth factor receptor), a surface protein on the cell, belongs to the tyrosine kinase family, responsible for cell growth and proliferation. Overexpression or mutation in the EGFR gene leads to various types of cancer, i.e., non-small cell lung cancer, breast, and pancreatic cancer. Bioactive molecules identified in this genre were also an essential source of encouragement for researchers who accomplished the design and synthesis of novel compounds with anticancer properties. World Health Organization (WHO) report states that antibiotic resistance is one of the most severe risks to global well-being, food safety, and development. The world needs to take steps to lessen this danger, such as developing new antibiotics and regulating their use. In this study, 6524 compounds derived from Streptomyces sp. were subjected to drug-likeness filters, molecular docking, and molecular dynamic simulation for 1000 ns to find new triple mutant EGFRCSTMLR (EGFR-L858R/T790M/C797S) inhibitors. Docking outcomes revealed that five compounds showed better binding affinity (− 9.074 to − 9.3 kcal/mol) than both reference drug CH7233163 (− 6.11 kcal/mol) and co-crystallized ligand Osimertinib (− 8.07 kcal/mol). Further, molecular dynamic simulation confirmed that ligand C_42 exhibited the best interaction at the active site of EGFR protein and comprised a better average radius of gyration (3.87 Å) and average SASA (Solvent Accessible Surface Area) (82.91 Å2) value than co-crystallized ligand (4.49 Å, 222.38 Å2). Additionally, its average RMSD (Root Mean Square Deviation) (3.25 Å) and RMSF (Root Mean Square Fluctuation) (1.54 Å) values were highly similar to co-crystallized ligand (3.07 Å, 1.54 Å). Compared to the reference ligand, it also demonstrated conserved H-bond interactions with the residues MET_793 and GLN_791 with strong interaction probability. In conclusion, we have found a potential drug with no violation of the rule of three, Lipinski's rule of five, and 26 other vital parameters having great potential in medicinal and pharmaceutical industries applications and can overcome synthetic drug issues. © 2023, The Author(s).
From nature to cancer therapy: Evaluating the Streptomyces clavuligerus secondary metabolites for potential protein kinase inhibitors
(John Wiley and Sons Inc, 2024) Ravi Saini; Sonali Kumari; Amit Singh; Abha Mishra
The study aimed to evaluate the antioxidant, protein kinase inhibitory (PKIs) potential, cytotoxicity activity of Streptomyces clavuligerus extract. DPPH assay revealed a robust free radical scavenging capacity (IC50 28.90 ± 0.24 µg/mL) of organic extract with a maximum inhibition percentage of 61 ± 1.04%. PKIs assay revealed the formation of a whitish bald zone by S. clavuligerus extracts which indicates the presence of PKIs. The cytotoxicity activity of organic fraction of extract through Sulforhodamine B assay on MCF-7, Hop-62, SiHa, and PC-3 cell lines demonstrated the lowest GI50 value against the MCF-7 cell line followed by the PC-3 cell line, showing potent growth inhibitory potential against human breast cancer and human prostate cancer cell line. HR-LCMS analysis identified multiple secondary metabolites from the organic and aqueous extracts of S. clavuligerus when incubated at 30°C under 200 rpm for 3 days. All the secondary metabolites were elucidated for their potential to inhibit RTKs by molecular docking, molecular dynamic simulation, MM/GBSA calculations, and free energy approach. It revealed the superior inhibitory potential of epirubicin (Epi) and dodecaprenyl phosphate-galacturonic acid (DPGA) against fibroblast growth factors receptor (FGFR). Epi also exhibited excellent inhibitory activity against the platelet-derived growth factor receptor (PDGFR), while DPGA effectively inhibited the vascular endothelial growth factor receptor. Additionally, the presence Epi in S. clavuligerus extract was validated through the HPLC technique. Thus, our findings highlight a superior inhibitory potential of Epi against FGFR and PDGFR RTKs than the FDA-approved drug. © 2023 Wiley Periodicals LLC.
Multivariate Investigation of Heavy Metals in the Groundwater for Irrigation and Drinking in Garautha Tehsil, Jhansi District, India
(Taylor and Francis Inc., 2020) Naseem Akhtar; M.I. Syakir; S.P. Rai; Ravi Saini; Neeraj Pant; M.T. Anees; Abdul Qadir; Usman Khan
Groundwater is an important source for drinking and irrigation purposes. Due to anthropogenic activities, heavy metals have been leaching due to industrial waste and agricultural activities to the groundwater causing pollution. The assessment of groundwater quality is necessary to reduce the pollution to acceptable levels. Therefore, the aim of this study is to investigate heavy metal concentrations in the groundwater of the villages of Garautha Tehsil, Jhansi where the anthropogenic activities are active. The groundwater samples were analyzed by inductively coupled plasma–mass spectrometry (ICP-MS) and the results were compared to the 2012 Bureau of Indian Standard limits. Three multivariate statistical methods were used to analyze the groundwater quality for irrigation and drinking purposes and to investigate the geological and hydrogeological processes. The results of principal component analysis (PCA) identified four factors responsible for the data structure by illuminating the total variance of 77.83% of the dataset. The majority of groundwater samples contained Al, Co, Cu, Mn, Ni, Cr, Pb, and Fe within the acceptable limits except at few locations. However, the Al, Fe, and Mn concentration were high at a few sites due to rock–water interactions, whereas the concentration of As, Cd, and Zn were lower than their respective permissible limits in all groundwater samples. Furthermore, the groundwater quality for the use of irrigation is found to be acceptable at 19 locations, with only one high result. © 2019, © 2019 Taylor & Francis Group, LLC.
Novel allosteric inhibitor to target drug resistance in EGFR mutant: molecular modelling and free energy approach
(Taylor and Francis Ltd., 2022) Amit Singh; Ravi Saini; Abha Mishra
Anticancer therapy targets Tyrosine kinase (TK) to inhibit signal transduction pathway that regulate various physiological and biochemical processes. Mutation in and around the catalytic domain may lead to conformational changes and activity. The first identified mutation leading to resistance against tyrosine kinase inhibitor (TKI) was observed when Thr at 790 replaced to Met in Epidermal Growth Factor Receptor (EGFR). Third generation EGFR-TKIs bind irreversibly to the Cysteine 797, (ATP-binding pocket). Mutation of Cys 797 to Ser residue (EGFRC797S) causes resistance to third generation TKI. The present study explores allosteric inhibitor of EGFRT790M+C797S mutant TK by molecular modelling techniques using 3,92,945 compounds of Zinc database. Molecular docking study revealed that ZINC000072404720 have similar binding pattern and MM/GBSA free energy as known allosteric inhibitor EAI045. RMSD of EGFRT790M+C797S bound to EAI045 and ZINC000072404720 were quite similar and in acceptable range. Hydrogen bonds after 150ns simulation was observed between Lys 745 and Asp 855 with EAI045 and novel inhibitor showed hydrogen bonding with Lys 745, Leu 788, Thr 854, Asp 855, Phe 856. MM/GBSA free energy was better (-84.09 Kcal/mol) known inhibitor EAI045b (-65.95 Kcal/mol). ZINC000072404720 fulfils drug likeliness property and did not violate Lipinski’s rule of five. © 2022 Informa UK Limited, trading as Taylor & Francis Group.