Browsing by Author "Debnath, Abhijit"
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PublicationArticle A Deep Dive into PDE5 Inhibition: Innovative Discoveries via Virtual Screening(Bentham Science Publishers, 2024) Debnath, Abhijit; Chaudhary, Hema; Sharma, Parul; Singh, Rajesh; Srivastava, ShikhaBackground: PDE5 inhibitors have had a surge in popularity over the last decade owing to their efficacy in the treatment of erectile dysfunction, coronary vasculopathy, and pulmonary arterial hypertension. These inhibitors exhibit competitive binding with phosphodiesterase type 5 and inhibit the hydrolysis of cyclic guanosine monophosphate, hence elevating the levels of cGMP in smooth muscle cells and prolonging the duration of an erection. However, due to production costs and side effects, further research is needed to discover new PDE5 inhibitors. Objectives: The study aimed to identify potent PDE5 inhibitors by employing the extensive application of computer-aided drug design. Methods: Three different databases, named Million Molecules Database, Natural Product Database, and NCI Database, have been screened, which has been followed by filtering based on various drug-likeness rules, docking, ADME, toxicity, consensus molecular docking, and 100 ns molecular dynamics simulation. Results: Three compounds (ZINC05351336, ZINC12030898, and ZINC17949426) have exhibited stable-binding characteristics at the active site of PDE5, demonstrating a robust binding affinity. These molecules have been found to possess drug-like capabilities, effective ADME features, low toxicity, and high stability. Conclusion: The study has delved into the realm of PDE5 inhibitors, which have been found to be effective in treating erectile dysfunction, but high production costs and side effects necessitate new ones. Through computer-aided drug design and screening, three compounds have been identified with promising binding characteristics, drug-appropriate properties, effective ADME profiles, mini-mal toxicity, and stability, making them potential candidates for future PDE5 inhibitors. © 2024 Bentham Science Publishers.PublicationArticle Discovery of Novel Cathepsin D Inhibitors by High-Throughput Virtual Screening(AMG Transcend Association, 2023) Debnath, Abhijit; Chaudhary, Hema; Kumar, Rajesh; Shokeen, Ankit; Khurana, RiyaCathepsin D (CatD) is a cancer-associated inflammation protein that plays an important role in cancer-associated inflammation, osteoarthritis, and various neurodegenerative diseases. CatD is genetically stable and does not easily develop drug resistance. Targeting CatD is an interesting strategy for both cancer therapy and cancer prevention. Thus, we have tried working on CatD as a therapeutic target in this research. To identify potent CatD inhibitors, we have screened the Million Molecules Database, Natural Product Database, and NCI Database. Top hits have been filtered based on various drug-likeness rules, followed by ADME profiling, toxicity prediction, and Consensus Molecular docking. Our research work resulted in three molecules: ZINC12198861 (-9.6 Kcal/mol), ZINC2438311 (-9.5 kcal/Mol), and ZINC14533276 (-8.9 kcal/mol) are stability-binding at the active site of CatD with strong binding affinity, drug-like properties, effective ADME properties, low toxicity, and high stability. Inhibiting CatD with these identified molecules will promote apoptosis and cure cancer-associated inflammation and osteoarthritis. © 2023 by the authors.PublicationArticle Discovery of novel CDK4/6 inhibitors from fungal secondary metabolites(Elsevier B.V., 2024) Debnath, Abhijit; Mazumder, Rupa; Singh, Rajesh Kumar; Singh, Anil KumarThe development of targeted therapies for breast cancer, particularly those focusing on cyclin-dependent kinases 4/6 (CDK4/6), has significantly improved patient outcomes. However, the currently approved CDK4/6 inhibitors are associated with various side effects, underscoring the need for novel compounds with enhanced efficacy and safety profiles. This study aimed to identify potential CDK4/6 inhibitors from MeFSAT, a database of fungal secondary metabolites using an in-silico screening approach. The virtual screening process incorporated drug-likeness filters, ADME and toxicity predictions, consensus molecular docking, and 200 ns molecular dynamics simulations. Out of 411 initial compounds, two molecules demonstrated favorable binding interactions and stability with the CDK4/6 protein complex. The MTT assay showed that MSID000025 had dose-dependent cytotoxicity against MCF7 breast cancer cells. This suggests that MSID000025 could be a good candidate CDK4/6 inhibitor for treating breast cancer. Our study highlights the potential of fungal secondary metabolites as a source of novel compounds for drug discovery. It provides a framework for identifying CDK4/6 inhibitors with improved therapeutic properties. © 2024 Elsevier B.V.PublicationArticle Discovery of novel HBV core protein inhibitors by high throughput virtual screening(Nature Research, 2025) Sanchitra, Jahanvi; Debnath, Abhijit; Singh, Anil kumar; Jha, Abhimanyu Kumar; Singh, Rajesh KumarHepatitis B Virus (HBV) constitutes a chronic viral infection with limited therapeutic options and a significant global health challenge. The virus lifecycle intricacy significantly relies on the core protein crucial for virus structure stability and interaction with host cells thus contributing to the infection’s persistence and severity. This study employs advanced techniques for the identification of novel core protein inhibitors through the screening of two chemical databases ZINC and BIMP utilizing computational methods such as structure-based virtual screening, drug-likeness, ADME, toxicity, consensus molecular docking, density functional theory, and 100 ns molecular dynamics simulation. The compound ZINC00674395 possesses high affinity and specificity towards core protein demonstrating drug-like properties, favorable ADME profiles, non-toxicity, and favorable electronic configuration with high stability at the core protein active site thus highlighting its potential as a therapeutic agent. These findings offer new insights into core protein interaction and pave the way for developing effective HBV therapeutics. © The Author(s) 2025.PublicationArticle Discovery of Novel PTP1B Inhibitors by High-throughput Virtual Screening(Bentham Science Publishers, 2025) Debnath, Abhijit; Rani, Anjna; Mazumder, Rupa; Mazumder, Avijit; Singh, Rajesh Kumar; Sharma, Shalini; Srivastava, Shikha; Chaudhary, Hema; Mishra, Rashmi; Khurana, Navneet; Sanchitra, Jahanvi; Jan, Sk AshifAim: To Discover novel PTP1B inhibitors by high-throughput virtual screening Background: Type 2 Diabetes is a significant global health concern. According to projections, the estimated number of individuals affected by the condition will reach 578 million by the year 2030 and is expected to further increase to 700 million deaths by 2045. Protein Tyrosine Phosphatase 1B is an enzymatic protein that has a negative regulatory effect on the pathways involved in insulin signaling. This regulatory action ultimately results in the development of insulin resistance and the subsequent elevation of glucose levels in the bloodstream. The proper functioning of insulin signaling is essential for maintaining glucose homeostasis, whereas the disruption of insulin signaling can result in the development of type 2 diabetes. Consequently, we sought to utilize PTP1B as a drug target in this investigation. Objective: The purpose of our study was to identify novel PTP1B inhibitors as a potential treatment for managing type 2 diabetes. Methods: To discover potent PTP1B inhibitors, we have screened the Maybridge HitDiscover database by SBVS. Top hits have been passed based on various drug-likeness rules, toxicity predictions, ADME assessment, Consensus Molecular docking, DFT, and 300 ns MD Simulations. Results: Two compounds have been identified with strong binding affinity at the active site of PTP1B along with drug-like properties, efficient ADME, low toxicity, and high stability. Conclusion: The identified molecules could potentially manage T2DM effectively by inhibiting PTP1B, providing a promising avenue for therapeutic strategies. © 2024 Bentham Science Publishers.PublicationArticle Experimental, quantum chemical spectroscopic investigation, topological, molecular docking/dynamics and biological assessment studies of 2,6-Dihydroxy-4-methyl quinoline(Elsevier B.V., 2025) Joshi, Rakesh Chandra; Husain, Shahid; Pandey, Nupur; Fatma, Nisha; Bisen, Divya; Upadhyay, Ratnakar; Debnath, Abhijit; Pant, Sanjay; Mishra, HirdyeshThe present work is a comprehensive investigation of the spectral, electronic structure, bonding, and reactivity of the 2,6-dihydroxy-4-methylquinoline (26DH4MQ) molecule through a wide range of experimental and quantum chemical spectroscopic calculations techniques, along with its applications as nonlinear optical materials and biological assessments. The study utilized density functional theory (DFT) and time-dependent density functional theory (TD-DFT) with the B3LYP method and the 6-311G++(d,p) basis set to analyze the structural and molecular properties of 26DH4MQ. The findings from UV–Vis, FT-IR, and FT-NMR spectroscopy show a strong agreement between the experimentally obtained vibrational frequencies and chemical shifts and those predicted by computational methods. Local reactivity descriptors, such as the dual descriptor, Fukui functions, and the molecular electrostatic potential (MEP) map, were used to identify the reactive regions of the molecule. Additionally, natural bond orbital (NBO) analysis provided insights into the charge transfer characteristics of 26DH4MQ, which helps to stabilize the molecular system. The study also revealed notable nonlinear optical (NLO) properties, with polarizability (18.52 × 10–24e.s.u.) and first-order hyperpolarizability (2.26 × 10–30e.s.u.) values that surpass those of standard organic compounds, suggesting significant potential for optoelectronic applications. The biological evaluation of 26DH4MQ assessed its drug-likeness, toxicity, enzyme inhibition, and ADME (Absorption, Distribution, Metabolism, and Excretion) parameters, highlighting its pharmaceutical potential. Furthermore, molecular docking and dynamics studies illustrated the compound's interaction with proteins, indicating its potential role as an insulin inhibitor. © 2024 Elsevier B.V.PublicationArticle Identification of novel cyclin-dependent kinase 4/6 inhibitors from marine natural products(Public Library of Science, 2025) Debnath, Abhijit; Mazumder, Rupa; Singh, Anil Kumar; Singh, Rajesh KumarCyclin-dependent kinases 4 and 6 (CDK4/6) are crucial regulators of cell cycle progression and represent important therapeutic targets in breast cancer. This study employs a comprehensive computational approach to identify novel CDK4/6 inhibitors from marine natural products. We utilized structure-based virtual screening of the CMNPD database and MNP library, followed by rigorous filtering based on drug-likeness criteria, PAINS filter, ADME properties, and toxicity profiles. From an initial hit of 9,497 compounds, 2,344 passed drug-likeness and PAINS filters. Further ADME filtering yielded 50 compounds, of which 25 exhibited non-toxic profiles. These 25 candidates underwent consensus molecular docking using seven distinct algorithms: AutoDockTools 4.2, idock, LeDock, Qvina 2, Smina, AutoDock Vina 1.2.0, PLANTS, and rDock. Based on these results, six top-scoring compounds were selected for comprehensive 500 nanosecond all-atom molecular dynamics simulations to evaluate their structural stability and interactions with CDK4/6. Our analysis revealed that compounds CMNPD11585 and CMNPD2744 demonstrated superior stability in their interactions with CDK4/6, exhibiting lower RMSD and RMSF values, more favorable binding free energies, and persistent hydrogen bonding patterns. These compounds also showed lower Solvent Accessible Surface Area values, indicating better compatibility with the CDK4/6 active site. Subsequent in-vitro studies using MTT assays on MCF-7 breast cancer cells confirmed the cytotoxic effects of these compounds, with CMNPD11585 showing the highest potency, followed by CMNPD2744. © 2025 Debnath et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.PublicationArticle In Search of Novel SGLT2 Inhibitors by High-throughput Virtual Screening(Bentham Science Publishers, 2024) Debnath, Abhijit; Sharma, Shalini; Mazumder, Rupa; Mazumder, Avijit; Singh, Rajesh; Kumar, Ankit; Dua, Arpita; Singhal, Priya; Kumar, Arvind; Singh, GurvinderBackground: Type 2 diabetes mellitus constitutes approximately 90% of all reported forms of diabetes mellitus. Insulin resistance characterizes this manifestation of diabetes. The prevalence of this condition is commonly observed in patients aged 45 and above; however, there is an emerging pattern of younger cohorts receiving diagnoses primarily attributed to lifestyle-related variables, including obesity, sedentary behavior, and poor dietary choices. The enzyme SGLT2 exerts a negative regulatory effect on insulin signaling pathways, resulting in the development of insulin resistance and subsequent elevation of blood glucose levels. The maintenance of glucose homeostasis relies on the proper functioning of insulin signaling pathways, while disruptions in insulin signaling can contribute to the development of type 2 diabetes. Objective: Our study aimed to identify novel SGLT2 inhibitors by high-throughput virtual Screening. Methods: We screened the May bridge Hit Discover database to identify potent hits followed by druglikeness, synthetic accessibility, PAINS alert, toxicity estimation, ADME assessment, and consensus molecular docking. Results: The screening process led to the identification of three molecules that demonstrated significant binding affinity, favorable drug-like properties, effective ADME, and minimal toxicity. Conclusion: The identified molecules could manage T2DM effectively by inhibiting SGLT2, providing a promising avenue for future therapeutic strategies. © 2024 Bentham Science Publishers.PublicationArticle In silico Identification of HDAC Inhibitors for Multiple Myeloma: A Structure-based Virtual Screening, Drug Likeness, ADMET Profiling, Molecular Docking, and Molecular Dynamics Simulation Study(Bentham Science Publishers, 2024) Debnath, Abhijit; Mazumder, Rupa; Mazumder, Avijit; Singh, Rajesh; Srivastava, ShikhaBackground: Multiple myeloma (MM) is a hematological malignancy of plasma cells that produce a monoclonal immunoglobulin protein. Despite significant advances in the treatment of MM, currently available therapies are associated with toxicity and resistance. As a result, there is an increasing demand for novel, effective therapeutics. Inhibition of histone deacetylases (HDACs) is emerging as a potential method for treating cancer. HDAC6 is one of 18 different HDAC isoforms that regulate tubulin lysine 40 and function in the microtubule network. HDAC6 participates in tumorigenesis and metastasis through protein ubiquitination, tubulin, and Hsp90. Several studies have found that inhibiting HDAC6 causes AKT and ERK dephosphorylation, which leads to decreased cell proliferation and promotes cancer cell death via the PI3K/AKT and MAPK/ERK signaling pathways. Objective: The objective of this study is to target HDAC6 and identify potent inhibitors for the treatment of multiple myeloma by employing computer-aided drug design. Materials and Methods: A total of 199,611,439 molecules from five different chemical databases, such as CHEMBL25, ChemSpace, Mcule, MolPort, and ZINC, have been screened against HDAC6 by structure-based virtual screening, followed by filtering for various drug-likeness, ADME, toxicity, consensus molecular docking, and 100 ns MD simulation. Results: Our research work resulted in three molecules that have shown strong binding affinity (CHEMBL2425964-9.99 kcal/mol, CHEMBL2425966-9.89 kcal/mol, and CSC067477144-9.86 kcal/mol) at the active site HDAC6, along with effective ADME properties, low toxicity, and high stability. Inhibiting HDAC6 with these identified molecules will induce AKT and ERK dephosphorylation linked to reduced cell proliferation and promote cancer cell death. Conclusion: CHEMBL2425964, CHEMBL2425966, and CSC067477144 could be effective against multiple myeloma. © 2024 Bentham Science Publishers.PublicationReview Molecular landscape of lung cancer: insights into therapeutic targets and clinical outcomes(Taylor and Francis Ltd., 2024) Mangal, Saloni; Debnath, Abhijit; Mazumder, Rupa; Mazumder, Avijit; Singh, Rajesh Kumar; Sanchitra, Jahanvi; Jan, S.K. Asif; Pandey, Pratibha; Kumar, Bimlesh; Singh, Anil KumarLung cancer is the leading cause of cancer-related deaths globally, accounting for 1.8 million fatalities in 2020. Genetic mutations, chromosomal abnormalities, transcription factors, mutations in tumor suppressor genes, and mutations in oncogenes have all been associated with an increased risk of LC development. Heterogeneity of the disease, resistance to chemotherapy, and side effects such as nausea and vomiting, fatigue, anemia, neuropathy, hair loss, and skin and nail changes are associated with conventional therapeutics such as chemotherapy, radiation therapy, and targeted therapy. Thus, the treatment of the disease urgently requires the discovery of novel therapeutic approaches. This review identifies and discusses key molecular and genetic targets for LC therapy, highlighting recent advancements and potential clinical applications. Our efforts encompass all biological targets and aim to increase our understanding of these processes to better comprehend the disease's molecular mechanisms and develop new drugs and more effective LC treatments. © 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.PublicationArticle Quest for discovering novel CDK12 inhibitor(Taylor and Francis Ltd., 2025) Debnath, Abhijit; Singh, Rajesh Kumar; Mazumder, Rupa; Mazumder, Avijit; Srivastava, Shikha; Chaudhary, Hema; Mangal, Saloni; Sanchitra, Jahanvi; Tyagi, Pankaj Kumar; Kumar Singh, Sachin; Singh, Anil KumarCDK12 is essential for cellular processes like RNA processing, transcription, and cell cycle regulation, inhibiting cancer cell growth and facilitating macrophage invasion. CDK12 is a significant oncogenic factor in various cancers, including HER2-positive breast cancer, Anaplastic thyroid carcinoma, Hepatocellular carcinoma, prostate cancer, and Ewing sarcoma. It is also regarded as a potential biomarker, emphasizing its broader significance in oncology. Targeting CDK12 offers a promising strategy to develop therapy. Various monoclonal antibodies have drawn wide attention, but they are expensive compared to small-molecule inhibitors, limiting their accessibility and affordability for patients. Consequently, this research aims to identify effective CDK12 inhibitors using comprehensive high-throughput virtual screening. RASPD protocol has been employed to screen three different databases against the target followed by drug-likeness, molecular docking, ADME, toxicity, Consensus molecular docking, MD Simulation, and in-vitro studies MTT assay. The research conducted yielded one compound ZINC11784547 has demonstrated robust binding affinity, favorable ADME features, less toxicity, remarkable stability, and cytotoxic effect. The identified compound holds promise for promoting cancer cell death through CDK12 inhibition. © 2024 Informa UK Limited, trading as Taylor & Francis Group.PublicationReview Targeting Undruggable Proteins: The siRNA Revolution Beyond Small Molecules - Advances, Challenges, and Future Prospects in Therapeutic Innovation(Bentham Science Publishers, 2025) Jan, SK Ashif; Debnath, Abhijit; Singh, Rajesh Kumar; Tyagi, Pankaj Kumar; Singh, Sachin; Singh, Anil KumarThe field of drug discovery has long been challenged by the existence of “undruggable” proteins - targets that have resisted traditional small molecule approaches due to their structural or functional characteristics. This review explores the revolutionary potential of small interfering RNA (siRNA) technology in addressing these elusive targets, marking a paradigm shift in therapeutic development. We discuss the historical development of siRNA technology and its unique mechanism of action, which allows for the silencing of virtually any gene, including those coding for proteins previously deemed undruggable. The review provides a comprehensive analysis of the challenges in targeting undruggable proteins and how siRNA approaches are overcoming these obstacles. We examine several case studies of undruggable targets being successfully addressed by siRNA, including oncogenic proteins like KRAS and c-Myc, transcription factors such as NF-κB and STAT3, and proteins involved in complex protein-protein interactions. The article delves into the latest advances in siRNA design, delivery systems, and targeting strategies, highlighting innovations that enhance specificity and reduce off-target effects. We also discuss the challenges facing siRNA therapeutics, including delivery obstacles, potential immune responses, and regulatory considerations. The review concludes with an exploration of future directions, including combination therapies, personalized medicine approaches, and emerging technologies that complement siRNA strategies. By providing a thorough examination of the advances, challenges, and prospects of using siRNA to target undruggable proteins, this review underscores the transformative potential of this technology in expanding the landscape of therapeutic targets and ushering in a new era of precision medicine. © 2025 Bentham Science Publishers.
