http://dspace.dtu.ac.in:8080/jspui/handle/123456789/37 2026-06-10T22:51:04Z http://dspace.dtu.ac.in:8080/jspui/handle/repository/22805 Title: STRUCTURE ACTIVITY RELATIONSHIP ANALYSIS OF MARINE PHLOROTANNINS AS SELECTIVE DPP-4 INHIBITORS: A COMPUTATIONAL PERSPECTIVE Authors: JUYAL, AMAN; Verma, Smita Rastogi (SUPERVISOR) Abstract: T2DM is a metabolic disorder affecting hundreds of thousands of people globally, characterized by insulin secretion and insulin resistance. DPP-4) has emerged as a clinically important pharmacological target in T2DM management, as its inhibition increases the half life of the hormone GLP-1, thereby enhancing insulin secretion. While synthetic DPP-4 inhibitors are clinically approved, their long-term use is associated with heart and pulmonary problems, along with high costs in developing countries. These problems have made it necessary to explore natural sources as inhibitors of DPP-4. Marine phlorotannins, natural phenolic compounds derived from brown algae, have demonstrated broad-spectrum activities including anti-diabetic, anti-inflammatory, and antioxidant properties. This thesis specifically investigates the SAR of five marine phlorotannins: phloroglucinol, eckol, dioxinodehydroeckol, fucodiphloroethol G, and phlorofucofuroeckol A as potential inhibitors of DPP-4, using in silico molecular docking as the tool of interest. Molecular docking was done using the AutoDock Vina algorithm via the PyRx virtual screening tool. The DPP-4 structure was obtained from the RCSB Protein Data Bank, and the ligand structure from PubChem. interactions between P-L were analyzed using BIOVIA Discovery Studio Visualizer, with a focus on interactions involving the catalytic residues Glu205, Glu206, Tyr662, Tyr666, and Trp659. The SAR analysis reveals a strong positive correlation between phlorotannin’s structural complexity, specifically the degree of polymerization, number of hydroxyl groups, and extent of aromatic ring fusion with binding affinity for DPP-4. Phlorofucofuroeckol A, the most complex compound studied, achieved the binding affinity of (−10.2 kcal/mol), better than the synthetic control sitagliptin (−9.2 kcal/mol). Further SAR analysis with different structural series shows that an increment in ring complexity corresponds to improvements in binding energy, selectivity of active-site engagement, and interaction with both the S1 and S2 substrate binding subsites. 2026-05-01T00:00:00Z http://dspace.dtu.ac.in:8080/jspui/handle/repository/22804 Title: MARINE PHLOROTANNINS AS LEAD CANDIDATES FOR DPP-4 INHIBITION: A COMPUTATIONAL DRUG DISCOVERY PIPELINE EVALUATION FOR TYPE 2 DIABETES THERAPEUTICS Authors: BORGOHAIN, ABHINAV; Verma, Smita Rastogi (SUPERVISOR) Abstract: The worldwide diabetes pandemic of Type 2 diabetes mellitus (T2DM) has become the most common metabolic disease which affects global populations as the number of affected individuals is expected to reach 700 million people by 2045. Dipeptidyl peptidase-4 (DPP-4) inhibitors, or gliptins, have emerged as an important pharmacological class for T2DM management by extending the bioavailability of endogenous glucagon-like peptide-1 (GLP-1). The three gliptins that exist on the market include sitagliptin and saxagliptin and linagliptin but these medications cause harmful effects and create financial difficulties for patients in low- and middle-income countries. This situation creates a need to study natural products because they might provide better safety and cheaper development expenses. Marine phlorotannins function as a unique type of polyphenolic compound which brown algae from the class Phaeophyceae use to create their own biosynthetic pathways. Marine phlorotannins show multiple biological activities which include their ability to fight diabetes and reduce inflammation and their antioxidant properties. The research team has not yet conducted a complete investigation into marine phlorotannins as potential lead substances for drug development. The thesis establishes an entire in silico drug discovery process assessment for five marine phlorotannins which include phloroglucinol, eckol, dioxinodehydroeckol, fucodiphloroethol G, and phlorofucofuroeckol A as they interact with DPP-4 found in humans. Through AutoDock Vina molecular docking which operates with PyRx software phlorofucofuroeckol A showed the strongest binding capacity because it achieved a binding energy of −10.2 kcal/mol which exceeded the binding energy of the FDA-approved drug sitagliptin which reached −9.2 kcal/mol. The protein ligand interaction analysis showed that BIOVIA Discovery Studio confirmed permanent binding with the DPP-4 active site through Glu205 Glu206 Tyr662 Tyr666 Trp659 catalytic residues. The researchers conducted extensive computational ADMET testing through SwissADME and pkCSM to evaluate all candidate phlorotannins. The drug-like properties of Phlorofucofuroeckol A meet both Lipinski and Veber standards and it shows predicted oral bioavailability which is considered acceptable together with a safe toxicity profile. The comparative assessment between this marine natural product and sitagliptin shows its potential for practical application. The combined research results establish phlorofucofuroeckol A as a strong candidate for molecular dynamics simulations and in vitro enzymatic validation studies. 2026-05-01T00:00:00Z http://dspace.dtu.ac.in:8080/jspui/handle/repository/22799 Title: IDENTIFICATION OF COMMON GENES, MIRNAS, AND TRANSCRIPTION FACTORS THROUGH COMPREHENSIVE NETWORK ANALYSIS FOR ENHANCED MANAGEMENT OF GASTRITIS AND STOMACH CANCER Authors: PAL, ANUSHKA; DAS, ASMITA (SUPERVISOR) Abstract: Gastritis is a condition marked by ongoing inflammation of the stomach lining. It is known to be a precursor to stomach cancer, or gastric carcinoma, which is a major cause of cancer-related deaths worldwide. This happens mainly because the disease is often detected late and progresses slowly. The shift from chronic issues like atrophic gastritis to cancer involves genetic mutations, changes in gene expression, and disrupted signaling pathways. Identifying common molecular mechanisms is critical for precise treatment and early intervention. This study uses a network-based bioinformatics approach to identify shared genes, microRNAs (miRNAs), and transcription factors that connect gastritis and stomach cancer. This could help improve clinical management of these gastric diseases. We gathered genes related to gastritis and stomach tumors from the Comparative Toxicogenomics Database (CTD). We selected the top 200 genes for each condition based on inference scores and analyzed them to find overlaps.Using NetworkAnalyst 3.0, we built networks to explore gene-miRNA interactions, co-expression specific to stomach tissue, and transcription factor-gene relationships. This revealed pathways involved in inflammation (like NF-κB signaling), cell cycle regulation, apoptosis, and oxidative stress. Key miRNAs affect groups of disease-related genes. Meanwhile, major transcription factors such as MYC, RELA, and STAT3 coordinate the shift from inflammation to cancer. These networks show strong connections and specific patterns related to the stomach.The findings highlight how gastritis can progress to cancer, suggesting that these regulators could serve as biomarkers for early detection, prognosis, and monitoring in at-risk individuals. Targeting these pathways could lead to timely interventions that prevent cancer transformation and improve patient outcomes through tailored diagnostics and treatments. 2026-05-01T00:00:00Z http://dspace.dtu.ac.in:8080/jspui/handle/repository/22798 Title: COMPUTATIONAL IDENTIFICATION OF NOVEL BACE1 MODULATORS FOR ALZHEIMER'S DISEASE: A STRUCTURE DRIVEN DRUG DISCOVERY APPROACH Authors: YADAV, SANJANA; Kumar, Pravir (SUPERVISOR) Abstract: Aim: Amyloid beta deposition in the neural tissue, which leads to neural detrioration and escalating cognitive deterioration are major signatures of Alzheimer disease, a chronic neurodegenerative disorder. Since BACE1 sparks the amyloidogenic pathway fueling Amyloid beta generation and plaque augmentation, inhibiting BACE 1 is a promising approach to curb its accumulation in AD. This study used a computational approach where 5HTZ a co crystallised molecular structure which showcases a potent inhibitor bound or complexed at the catalytic pocket or binding site of the BACE1 was utilized as reference structure to find promising BACE 1 inhibitors. The primary objective was to shortlist better suited compounds for BACE 1 inhibition and thus Alzheimer treatment to that was formely found. Here, a large number of compounds were Shortlisted on the basis of structural similarity to the reference molecule which Were filtered by ADME analysis. A carefully chosen compound library was docked into the catalytic pocket of BACE1 after protein preparation and active-site mapping in order to assess interaction potency and interaction stability. Top hits having strong interactions with key residues were profiled for ADME, including drug –likeness, GI absorption, BBB permeability and CNS relevant characteristics. Numerous compounds demonstrated advantageous pharmacokinetic profiles and binding energies, making them prime candidates for pharmacological and biochemical verification. These findings supports the use of computational techniques to accelerate the discovery of novel BACE1 modulators for the disease. Further they also highlight promising lead candidates to carry out additional trial and confirmation. Keywords— Alzheimers disease, BACE1, amyloid beta generation, virtual screening, ADME analysis, catalytic pocket, active site mapping, pharmacokinetic profiles, computational strategies. Result: During the course of this study, an initial pool of 400 structurally similar compounds was screened, from which ADME evaluation refined the selection to 81 candidates, all exhibiting blood–brain barrier permeability. Subsequent molecular docking analysis revealed that five of these compounds demonstrated stronger binding affinities than the reference compound ,with the top-performing compound showing a binding affinity of −8.7 kcal/mol. Conclusion: From the set of five shortlisted candidates, Compound 5 demonstrated the strongest performance, showing the highest binding affinity along with the ability to cross the blood–brain barrier. Further validation of these results through in vivo studies is recommended to confirm its potential. 2026-05-01T00:00:00Z