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Item In silico evaluation of bisphosphonates identifies leading candidates for SARS-CoV-2 RdRp inhibition(Elsevier, 2025-05) Garg, Mohit; Murugesan, SankaranarayananThe novel coronavirus disease (COVID-19) pandemic has resulted in 777 million confirmed cases and over 7 million deaths worldwide, with insufficient treatment options. Innumerable efforts are being made around the world for faster identification of therapeutic agents to treat the deadly disease. Post Acute Sequelae of SARS-CoV-2 infection or COVID-19 (PASC), also called Long COVID, is still being understood and lacks treatment options as well. A growing list of drugs are being suggested by various in silico, in vitro and ex vivo models, however currently only two treatment options are widely used: the RNA-dependent RNA polymerase (RdRp) inhibitor remdesivir, and the main protease inhibitor nirmatrelvir in combination with ritonavir. Computational drug development tools and in silico studies involving molecular docking, molecular dynamics, entropy calculations and pharmacokinetics can be useful to identify new targets to treat COVID-19 and PASC, as shown in this work and our recent paper that identified alendronate as a promising candidate. In this study, we have investigated all bisphosphonates (BPs) on the ChEMBL database which can bind competitively to nidovirus RdRp-associated nucleotidyl (NiRAN) transferase domain, and systematically down selected seven candidates (CHEMBL608526, CHEMBL196676, CHEMBL164344, CHEMBL4291724, CHEMBL4569308, CHEMBL387132, CHEMBL98211), two of which closely resemble the approved drugs minodronate and zoledronate. This work and our recent paper together provide an in silico mechanistic explanation for alendronate and zoledronate users having dramatically reduced odds of SARS-CoV-2 testing, COVID-19 diagnosis, and COVID-19-related hospitalizations, and indicate that similar observational studies in Japan with minodronate could be valuable.Item Inspection of in-house designed novel thiochromone amino-acid conjugate derivatives as Lm-NMT inhibitor – An in-silico analysis(Elsevier, 2023-03) Murugesan, SankaranarayananLeishmaniasis is a complex neglected tropical disease caused by various leishmanial parasites that primarily affect the world's poorest people. A limited number of standard medications are available for this disease that has been used for several decades, which have drawbacks such as resistance, higher cost, and patient compliance, making it difficult to reach the poor. The search for novel chemical entities to treat leishmaniasis has led to target-based scaffold research. Thiochromone moieties in conjugation with aromatic amino acids have been considered for the study, along with possible substitutions of the electron-withdrawing and electron-donating groups. N-myristoyl transferase (NMT) has been selected as the molecular target for the study responsible for protein-protein interaction and ribosylation of proteins necessary for the growth inside the human body of the parasite. The designed novel thiochromone analogs were docked against the selected leishmanial NMT using the in-silico methods, physicochemical and toxicity properties were predicted, and Structure-Activity Relationship was also established in-silico. Finally, a molecular dynamics simulation study for 100 ns gave an idea about the stability of the protein-ligand complex. A time frame analysis of each 10 ns confirmation was also studied to understand better the putative binding pattern designed analogs.Item Synthesis, anti-acetylcholinesterase evaluation, molecular docking and molecular dynamics simulation of novel psoralen derivatives(Bentham Science, 2024-02) Murugesan, SankaranarayananSeven new psoralen derivatives were synthesised by carbodiimide coupling to active carboxylic acid to amide formation in mild reaction conditions. Methods: The psoralen derivatives were produced through the condensation of seven different types of amine groups consisting of electron withdrawing groups and electron donating groups. Results: All the synthesised compounds were obtained with moderate to high yields. Structural characterization using ATR-FTIR, 1H NMR, 13C NMR, and HRMS has confirmed their structure. Moreover, in silico evaluation of the psoralen derivatives against the AChE enzyme was performed, and acetylcholinesterase inhibitory activity of psoralen derivatives was also conducted. Conclusion: Results from molecular docking show the potential of compound 12e as AChE inhibitors due to its highest binding energy value. It was further supported by the antiacetylcholinesterase activity of compound 12e, which has 91.69% inhibition, comparable to galantamine (94.12%). Furthermore, 100 ns run molecular dynamics (MD) simulation was used to refine docking results.Item Molecular docking and dynamics identify potential drugs to be repurposed as sars-cov-2 inhibitors(World Scientific, 2024) Murugesan, SankaranarayananThe novel coronavirus disease 19 (COVID-19) has resulted in an estimated 20 million excess deaths and the recent resurgence of COVID-19 in China is predicted to result in up to 1 million deaths over the next few months. With vaccines being ineffective in the case of immunocompromised patients, it is important to continue our quest for safe, effective and affordable drugs that will be available to all countries. Drug repurposing is one of the strategies being explored in this context. Recently, out of the 7817 drugs approved worldwide, 214 candidates were systematically down-selected using a combination of 11 filters including FDA/TGA approval status, assay data against SARS-CoV-2, pharmacokinetic, pharmacodynamic and toxicity profiles. These down-selected drugs were subjected in this study to virtual screening against various SARS-CoV-2 targets followed by molecular dynamics studies of the best scoring ligands against each target. The chosen molecular targets were spike receptor binding domain, nucleocapsid protein RNA binding domain and key nonstructural proteins 3, 5 and 12–14. Four drugs approved for other indications — alendronate, cromolyn, natamycin and treprostinil — look sufficiently promising from our in-silico studies to warrant further in-vitro and in-vivo investigations as appropriate to ascertain their extent of antiviral activities.Item Molecular docking and in silico adme(t) evaluation of selective phytochemical inhibitors of vegf2 target for the treatment of diabetic retinopathy(Bentham Science, 2024-10) Murugesan, SankaranarayananDiabetic retinopathy (DR) is the leading cause of vision loss in diabetic patients. Currently, the treatment involves the use of glucocorticoids or a VEGF antagonist, which are “off-label” at present. However, the conventional method of drug discovery and development is a time-consuming process that requires more than a decade of meticulous research and huge financial support. While there are a few effective small organic molecules against DR that were identified many years ago, nutraceuticals - naturally available functional foods containing vitamins, antioxidants, minerals, fatty acids, and amino acids - can also help delay the progression of some diseases.