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Item Unraveling PPARβ/δ nuclear receptor agonists via a drug-repurposing approach: HTVS-based ligand identification, molecular dynamics, pharmacokinetics, and in vitro anti-steatotic validation(RSC, 2025-04) Sharma, Pankaj Kumar; Murugesan, Sankaranarayanan; Deepa, P.R.Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors with a crucial regulatory role in carbohydrate and lipid metabolism and are emerging druggable targets in “metabolic syndrome” (MetS) and cancers. However, there is a need to identify ligands that can activate specific PPAR subtypes, particularly PPARβ/δ, which is less studied compared with other PPAR isoforms (α and γ). Herein, using the drug-repurposing approach, the ZINC database of clinically approved drugs was screened to target the PPARβ/δ receptor through high-throughput-virtual-screening, followed by molecular docking and molecular dynamics (MD) simulation. The top-scoring ligands were subjected to drug-likeness analysis. The hit molecule was tested in an in vitro model of NAFLD (non-alcoholic fatty liver disease). The top five ligands with strong binding affinity towards PPARβ/δ were canagliflozin > empagliflozin > lumacaftor > eprosartan > dapagliflozin. RMSD/RMSF analysis demonstrated stable protein–ligand complexation (PLC) by the top-scoring ligands with PPARβ/δ. In silico ADMET prediction analysis revealed favorable pharmacokinetic profiles of these top five ligands. Canagliflozin showed significant (P < 0.001) dose-dependent decrease in lipid accumulation and the associated oxidative stress-inflammatory response, suggesting its promising anti-steatotic potential. These outcomes pave the way for further validation and development of PPAR activity-modulating therapeuticsItem Pharmacophore modelling-based drug repurposing approaches for monkeypox therapeutics(Taylor & Francis, 2022-09) Murugesan, SankaranarayananMonkeypox is a zoonotic viral disease that mainly affects tropical rainforest regions of central and west Africa, with sporadic exportations to other places. Since there is no cure, treating monkeypox with an antiviral drug developed for smallpox is currently acceptable. Our study mainly focused on finding new therapeutics to target monkeypox from existing compounds or medications. It is a successful method for discovering or developing medicinal compounds with novel pharmacological or therapeutic applications. In this study, homology modelling developed the Monkeypox VarTMPK (IMNR) structure. Ligand-based pharmacophore was generated using the best docking pose of standard ticovirimat. Further, molecular docking analysis showed compounds, tetrahydroxycurcumin, procyanidin, rutin, vicenin-2, kaempferol 3-(6''-malonylglucoside) were the top five binding energy compounds against VarTMPK (1MNR). Furthermore, we carried out MD simulations for 100 ns for the six compounds, including reference based on the binding energies and interactions. MD studies revealed that as ticovirimat interacted with residues Lys17, Ser18, and Arg45, all the above five compounds interacted with the same amino acids at the active site during docking and simulation studies. Among all the compounds, ZINC4649679 (Tetrahydroxycurcumin) was shown to have the highest binding energy −9.7 kcal/mol and also observed stable protein-ligand complex during MD studies. ADMET profile estimation showed that the docked phytochemicals were safe. However, further biological assessment through a wet lab is essential to measure the efficacy and safety of the compounds.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 Use of Human Lung Tissue Models for Screening of Drugs against SARS-CoV-2 Infection(MDPI, 2022-10) Murugesan, SankaranarayananThe repurposing of licenced drugs for use against COVID-19 is one of the most rapid ways to develop new and alternative therapeutic options to manage the ongoing pandemic. Given circa 7817 licenced compounds available from Compounds Australia that can be screened, this paper demonstrates the utility of commercially available ex vivo/3D airway and alveolar tissue models. These models are a closer representation of in vivo studies than in vitro models, but retain the benefits of rapid in vitro screening for drug efficacy. We demonstrate that several existing drugs appear to show anti-SARS-CoV-2 activity against both SARS-CoV-2 Delta and Omicron Variants of Concern in the airway model. In particular, fluvoxamine, as well as aprepitant, everolimus, and sirolimus, has virus reduction efficacy comparable to the current standard of care (remdesivir, molnupiravir, nirmatrelvir). Whilst these results are encouraging, further testing and efficacy studies are required before clinical use can be consideredItem CoviRx: A User-Friendly Interface for Systematic Down-Selection of Repurposed Drug Candidates for COVID-19(MDPI, 2022-11) Murugesan, SankaranarayananAlthough various vaccines are now commercially available, they have not been able to stop the spread of COVID-19 infection completely. An excellent strategy to get safe, effective, and affordable COVID-19 treatments quickly is to repurpose drugs that are already approved for other diseases. The process of developing an accurate and standardized drug repurposing dataset requires considerable resources and expertise due to numerous commercially available drugs that could be potentially used to address the SARS-CoV-2 infection. To address this bottleneck, we created the CoviRx.org platform. CoviRx is a user-friendly interface that allows analysis and filtering of large quantities of data, which is onerous to curate manually for COVID-19 drug repurposing. Through CoviRx, the curated data have been made open source to help combat the ongoing pandemic and encourage users to submit their findings on the drugs they have evaluated, in a uniform format that can be validated and checked for integrity by authenticated volunteers. This article discusses the various features of CoviRx, its design principles, and how its functionality is independent of the data it displays. Thus, in the future, this platform can be extended to include any other disease beyond COVID-19.Item Molecular Docking and Dynamics Identifies Potential Repurposed Drug Candidates for COVID-19 Studies(2023-01) 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 unable to halt transmission it is important to continue our quest for safe, effective, affordable drugs that will be available to all countries. Drug repurposing is one of the strategies being explored in this context. Recently, out of 7,817 approved drugs, 214 candidates were systematically down-selected using a combination of 11 filters including approval status, assay data against SARS-CoV-2, pharmacokinetic, pharmacodynamic and toxicity profiles. These drugs were subjected in this study to virtual screening against various targets of SARS-CoV-2 followed by molecular dynamic 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 non-structural proteins 3, 5, 12, 13 and 14. Four drugs approved for other indications — alendronate, cromolyn, natamycin and treprostinil — look sufficiently promising from our in silicostudies to warrant further in vitro and in vivo investigations as appropriate to ascertain their extent of anti-viral activities.Item Further Investigations of Nitroheterocyclic Compounds as Potential Antikinetoplastid Drug Candidates(MDPI, 2023-04) Murugesan, SankaranarayananDue to the lack of specific vaccines, management of the trypanosomatid-caused neglected tropical diseases (sleeping sickness, Chagas disease and leishmaniasis) relies exclusively on pharmacological treatments. Current drugs against them are scarce, old and exhibit disadvantages, such as adverse effects, parenteral administration, chemical instability and high costs which are often unaffordable for endemic low-income countries. Discoveries of new pharmacological entities for the treatment of these diseases are scarce, since most of the big pharmaceutical companies find this market unattractive. In order to fill the pipeline of compounds and replace existing ones, highly translatable drug screening platforms have been developed in the last two decades. Thousands of molecules have been tested, including nitroheterocyclic compounds, such as benznidazole and nifurtimox, which had already provided potent and effective effects against Chagas disease. More recently, fexinidazole has been added as a new drug against African trypanosomiasis. Despite the success of nitroheterocycles, they had been discarded from drug discovery campaigns due to their mutagenic potential, but now they represent a promising source of inspiration for oral drugs that can replace those currently on the market. The examples provided by the trypanocidal activity of fexinidazole and the promising efficacy of the derivative DNDi-0690 against leishmaniasis seem to open a new window of opportunity for these compounds that were discovered in the 1960s. In this review, we show the current uses of nitroheterocycles and the novel derived molecules that are being synthesized against these neglected diseases