Faculty Publications
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Item In Silico Studies of (Z)-3-(2-Chloro-4-Nitrophenyl)-5-(4-Nitrobenzylidene)-2-Thioxothiazolidin-4-One Derivatives as PPAR-γ Agonist: Design, Molecular Docking, MM-GBSA Assay, Toxicity Predictions, DFT Calculations and MD Simulation Studies(World Scientific, 2024) Gowdru Srinivasa, M.G.; Naik, S.; Udayakumar, U.; Mehta, C.H.; Nayak, U.Y.; Revanasiddappa, B.C.Diabetes mellitus, a metabolic disorder, arises from insufficient insulin levels or increased insulin resistance. An alternative approach to address this pathogenesis involves targeting PPAR-γ, which activates glucose homeostasis and improves peripheral glucose utilization. In this study, we aimed to investigate the designed 2-thioxothiazolidin-4-one derivatives (T1-25) and assess their potential as PPAR-γ regulators by an in silico approach. Physicochemical properties and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiles were evaluated. Docking studies were performed using Schrödinger software, with the protein target being PPAR-γ (PDB ID: 2ZNO). Additionally, MD simulation studies were conducted, and the key interactions in the protein-ligand complexes were identified. The results demonstrate the drug-likeness of compounds T11, T24 and T25, with docking scores of -7.953 kcal/mol, -7.973 kcal/ mol and -8.212 kcal/mol, respectively, and exhibit significant activity against PPAR-γ agonist and compared with the standard drug Pioglitazone (-7.367 kcal/mol). The density functional calculations were also performed to determine the geometrical properties, thermal parameters, chemical reactivity descriptors and molecular electrostatic potential of the compounds using the B3LYP functional and 6-31G++ basis sets. The energy difference between the highest occupied molecular orbitals and lowest unoccupied molecular orbitals for all the investigated compounds is in the range of 2.8-3.4 eV which allows for easy transfer of electrons and reactivity. Further research and development of these designed compounds could contribute to the advancement of effective antidiabetic treatments. © 2024 World Scientific Publishing Company.Item Structure-based drug design and characterization of novel pyrazine hydrazinylidene derivatives with a benzenesulfonate scaffold as noncovalent inhibitors of DprE1 tor tuberculosis treatment(Springer Nature, 2024) Naik, S.; Dinesha, P.; Udayakumar, D.In this study, we present a novel series of (E)-4-((2-(pyrazine-2-carbonyl) hydrazineylidene)methyl)phenyl benzenesulfonate (T1-T8) and 4-((E)-(((Z)-amino(pyrazin-2-yl)methylene)hydrazineylidene)methyl)phenyl benzenesulfonate (T9-T16) derivatives which exert their inhibitory effects on decaprenylphosphoryl-?-D-ribose 2'-epimerase (DprE1) through the formation of hydrogen bonds with the pivotal active site Cys387 residue. Their effectiveness against the M. tuberculosis H37Rv strain was examined and notably, three compounds (namely T4, T7, and T12) exhibited promising antitubercular activity, with a minimum inhibitory concentration (MIC) of 1.56 µg/mL. The target compounds were screened for their antibacterial activity against a range of bacterial strains, encompassing S. aureus, B. subtilis, S. mutans, E. coli, S. typhi, and K. pneumoniae. Additionally, their antifungal efficacy against A. fumigatus and A. niger also was scrutinized. Compounds T6 and T12 demonstrated significant antibacterial activity, while compound T6 exhibited substantial antifungal activity. Importantly, all of these active compounds demonstrated exceedingly low toxicity without any adverse effects on normal cells. To deepen our understanding of these compounds, we have undertaken an in silico analysis encompassing Absorption, Distribution, Metabolism, and Excretion (ADME) considerations. Furthermore, molecular docking analyses against the DprE1 enzyme was conducted and Density-Functional Theory (DFT) studies were employed to elucidate the electronic properties of the compounds, thereby enhancing our understanding of their pharmacological potential. © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2024.Item Benzothiazole derivatives as p53-MDM2 inhibitors: in-silico design, ADMET predictions, molecular docking, MM-GBSA Assay, MD simulations studies(Taylor and Francis Ltd., 2025) Shridhar Deshpande, N.; Naik, S.; Udayakumar, U.; Ghate, S.D.; Dixit, S.R.; Awasthi, A.; Revanasiddappa, B.C.Breast cancer stands as the most prevalent malignancy among the female populace. One of the pivotal domains in the therapeutic landscape of breast cancer revolves around the precise targeting of the p53-MDM2 inhibitory pathway. The advent of p53-MDM2 inhibition in the context of developing treatments for breast cancer marks a significant stride. In the quest for enhancing the efficacy of p53-MDM2 inhibition against breast cancer, a new series of benzothiazole compounds (B1-B30) was designed through in-silico methodologies in the present work. Using Schrodinger Maestro, the compounds underwent molecular docking assessments against the p53-MDM2 target (PDB: 4OGT). Compared to reference compounds, B25 and B12 exhibited notably elevated glide scores. Extensive in-silico studies, including ADMET and toxicity evaluations, were performed to predict pharmacokinetics, drug likeness, and toxicity. All compounds adhered to Lipinski criteria, signifying favorable oral drug properties. The MM-GBSA analysis indicated consistent binding free energies. Molecular dynamics simulations for B25 over 200 ns assessed complex stability and interactions. In summary, these compounds exhibit potential for future cancer therapy medication development. © 2023 Informa UK Limited, trading as Taylor & Francis Group.Item Noncovalent inhibitors of DprE1 for tuberculosis treatment: design, synthesis, characterization, in vitro and in silico studies of 4-oxo-1,4-dihydroquinazolinylpyrazine-2-carboxamides(Taylor and Francis Ltd., 2025) Naik, S.; Dinesha, P.; Udayakumar, U.In this study, we present a novel series of 4-oxo-1,4-dihydroquinazolinylpyrazine-2-carboxamide derivatives, which exert their inhibitory effect on decaprenylphosphoryl-?-D-ribose 2’-epimerase (DprE1) via the establishment of non-covalent interactions with the pivotal Cys387 residue located within the enzyme’s active site. These compounds underwent scrutiny for their efficacy in combatting the Mycobacterium tuberculosis H37Rv strain, and compounds T8 and T13 exhibited promising antitubercular activity, boasting a minimal inhibitory concentration (MIC) of 7.99 and 8.27 µM respectively. Additionally, three compounds, T2, T3 and T12, showcased substantial antibacterial activity whereas compounds T12 and T13 exhibited pronounced antifungal efficacy. Remarkably, all active compounds demonstrated negligible cytotoxicity, and none posed harm to normal cells. To attain a more profound comprehension of the attributes of these compounds, we conducted in silico investigations to evaluate their Absorption, Distribution, Metabolism and Excretion properties. Additionally, molecular docking analyses were executed to elucidate their interactions with the DprE1 enzyme. Finally, Density Functional Theory studies were leveraged to explore the electronic characteristics of these compounds, thereby providing insights into their potential utility in the realm of pharmaceuticals. © 2024 Informa UK Limited, trading as Taylor & Francis Group.