In-vitro antiviral activity and in-silico targeted study of quinoline-3-carboxylate derivatives against SARS-Cov-2 isolate.

In recent years, the viral outbreak named COVID-19 showed that infectious diseases have a huge impact on both global health and the financial and economic sectors. The lack of efficacious antiviral drugs worsened the health problem. Based on our previous experience, we investigated in vitro and in silico a series of quinoline-3-carboxylate derivatives against a SARS-CoV-2 isolate. In the present study, the in-vitro antiviral activity of a series of quinoline-3-carboxylate compounds and the in silico target-based molecular dynamics (MD) and metabolic studies are reported. The compounds' activity against SARS-CoV-2 was evaluated using plaque assay and RT-qPCR. Moreover, from the docking scores, it appears that the most active compounds (1j and 1o) exhibit stronger binding affinity to the primary viral protease (NSP5) and the exoribonuclease domain of non structural protein 14 (NSP14). Additionally, the in-silico metabolic analysis of 1j and 1o defines CYP2C9 and CYP3A4 as the major P450 enzymes involved in their metabolism.

Targeting lipid-sensing nuclear receptors PPAR (α, γ, ß/δ): HTVS and molecular docking/dynamics analysis of pharmacological ligands as potential pan-PPAR agonists.

The global prevalence of obesity-related systemic disorders, including non-alcoholic fatty liver disease (NAFLD), and cancers are rapidly rising. Several of these disorders involve peroxisome proliferator-activated receptors (PPARs) as one of the key cell signaling pathways. PPARs are nuclear receptors that play a central role in lipid metabolism and glucose homeostasis. They can activate or suppress the genes responsible for inflammation, adipogenesis, and energy balance, making them promising therapeutic targets for treating metabolic disorders. In this study, an attempt has been made to screen novel PPAR pan-agonists from the ZINC database targeting the three PPAR family of receptors (α, γ, ß/δ), using molecular docking and molecular dynamics (MD) simulations. The top scoring five ligands with strong binding affinity against all the three PPAR isoforms were eprosartan, canagliflozin, pralatrexate, sacubitril, olaparib. The ADMET analysis was performed to assess the pharmacokinetic profile of the top 5 molecules. On the basis of ADMET analysis, the top ligand was subjected to MD simulations, and compared with lanifibranor (reference PPAR pan-agonist). Comparatively, the top-scoring ligand showed better protein-ligand complex (PLC) stability with all the PPARs (α, γ, ß/δ). When experimentally tested in in vitro cell culture model of NAFLD, eprosartan showed dose dependent decrease in lipid accumulation and oxidative damage. These outcomes suggest potential PPAR pan-agonist molecules for further experimental validation and pharmacological development, towards treatment of PPAR-mediated metabolic disorders.

Presenting a new fluorescent probe, methyl(10-phenylphenanthren-9-yl)sulfane sensitive to the polarity and rigidity of the microenvironment: applications toward microheterogeneous systems.

A molecule, methyl(10-phenylphenanthren-9-yl)sulfane (MPPS), with a straightforward structure, has been synthesized, characterized, and explored as a new fluorescent probe for microheterogeneous systems. The photophysical properties of MPPS have been studied through experimental and theoretical calculations using the range-separated hybrid functional CAM-B3LYP in conjunction with a 6-311++g(d,p) basis set. Theoretical calculations show that the freely rotating phenyl ring forms a 94° dihedral angle with the phenanthrene ring in the ground state. Experimentally found two absorption bands correspond to the n → π* and π → π* transitions supported by the frontier molecular orbital calculations. Two excited singlet states, E-1 and E-2 (the former being more stable than the latter in the gas phase), exist with dihedral angles between the phenyl and phenanthrene rings as 142° and 133°, respectively, in the gas phase. Two emitting states in a condensed medium of varying polarities are supported by the steady-state fluorescence and fluorescence intensity decay data. Emission energies, fluorescence intensities, and excited singlet state lifetimes change with the polarity of the solvents. To support that the free rotation in the molecule is responsible for these changes, the fluorescence properties of another molecule, methyl(10-(o-tolyl)phenanthren-9-yl)sulfane (MTPS), with restricted rotation of the substituted benzene, i.e., o-tolyl ring have been studied. The fast-intensity decay component of MPPS is ascribed to the conformer in the E-1 state. The molecule has proved to be an excellent polarity probe explored to determine the critical micelle concentrations (cmc) values of different surfactants, which agree well with the literature reports. Different regions of binding isotherm (specific, non-cooperative, cooperative, and massive binding) of a gemini surfactant, 12-6-12,2Br- with bovine serum albumin (BSA) have been successfully demonstrated by the steady-state and time-resolved fluorescence and fluorescence anisotropic properties of MPPS. Docking results show that MPPS resides in the hydrophobic pocket of BSA. The fluorescence quenching of BSA by MPPS reveals the location of Trp residues of BSA. Thus, a polarity and molecular rigidity-sensitive fluorescent molecule, MPPS has been presented here that can potentially be used to monitor the changes in the microenvironment of biomolecules in different processes.

Identification of Potential Inhibitors from Medicinal Plant-based Phytochemicals for the Influential C4 Target of Diabetic Retinopathy by Molecular Docking Studies.

INTRODUCTION: Diabetic retinopathy is the major cause of vision failure in diabetic patients, and the current treatment involves the practice of glucocorticoids or VEGF antagonists that are "off-label". A few small organic molecules against DR were discovered many years ago. Nutraceuticals are naturally available functional foods that endorse different health benefits, including vitamins, antioxidants, minerals, fatty acids, and amino acids that can defer the development of some diseases. METHODS: Numerous studies reported that nutraceuticals encourage multiple therapeutic benefits and provide protection against various diseases. In diabetes, nutraceuticals contribute to improving insulin sensitivity, metabolism regulation, and lower hyperglycemia. The major aim of this study is to discover the most active drug from natural or plant sources. In this work, 42 phytochemical constituents from 4 kinds of plants were docked with the C4 target of diabetic retinopathy by an in silico molecular docking study. RESULTS: According to the binding energy, all the phytoconstituents possessed good to high attraction towards the target, and 6 phytochemicals, such as terchebulin, punicalagin, chebulagic acid, casuarinin, punicalin, and pedunculagin, disclosed superior binding energy towards the target than standard ruboxistaurin via the interactions of conventional hydrogen bonding, pi-alkyl interactions, etc. Molecular dynamic simulation studies further established the stability of the phytoconstituents, and ADMET studies proved the safety profile of these phytoconstituents. CONCLUSION: Hence, the current study suggested that the phytochemicals from various herbs inhibit the C4 target of diabetic retinopathy and can be utilized as lead compounds to develop analogs or repurposed for the treatment of DR.

Computational Screening of Some Phytochemicals to Identify Best Modulators for Ligand Binding Domain of Estrogen Receptor Alpha.

OBJECTIVE: The peculiar aim of this study is to discover and identify the most effective and potential inhibitors against the most influential target ERα receptor by in silico studies of 45 phytochemicals from six diverse ayurvedic medicinal plants. METHODS: The molecular docking investigation was carried out by the genetic algorithm program of AutoDock Vina. The molecular dynamic (MD) simulation investigations were conducted using the Desmond tool of Schrödinger molecular modelling. This study identified the top ten highest binding energy phytochemicals that were taken for drug-likeness test and ADMET profile prediction with the help of the web-based server QikpropADME. RESULTS: Molecular docking study revealed that ellagic acid (-9.3 kcal/mol), emodin (-9.1 kcal/mol), rhein (-9.1 kcal/mol), andquercetin (-9.0 kcal/mol) phytochemicals showed similar binding affinity as standard tamoxifen towards the target protein ERα. MD studies showed that all four compounds possess comparatively stable ligand-protein complexes with ERα target compared to the tamoxifen-ERα complex. Among the four compounds, phytochemical rhein formed a more stable complex than standard tamoxifen. ADMET studies for the top ten highest binding energy phytochemicals showed a better safety profile. CONCLUSION: Additionally, these compounds are being reported for the first time in this study as possible inhibitors of ERα for treating breast cancer, according to the notion of drug repurposing. Hence, these phytochemicals can be further studied and used as a parent core molecule to develop innovative lead molecules for breast cancer therapy.

Retrospective Review of Chromane Analogues as Anti-protozoal Leads: A Decade's Worth of Evolution.

Tropical, vector-borne, and neglected diseases with a limited number of medication therapies include Leishmaniasis, Malaria, Chagas and Human African Trypanosomiasis (HAT). Chromones are a large class of heterocyclic compounds with significant applications. This heterocycle has long aroused the interest of scientists and the general public from biosynthetic and synthetic points of view owing to its interesting pharmacological activities. Chromones and their hybrids and isomeric forms proved to be an exciting scaffold to investigate these diseases. The in vitro activities of Chromone, Chromane, and a panel of other related benzopyran class compounds against Trypanosoma brucei rhodesiense, Trypanosoma brucei gambiense, Trypanosoma cruzi, and numerous Leishmanial and Malarial species were investigated in our previous studies. The current article briefly describes the neglected diseases and the current treatment. This review aims to attempt to find better alternatives by scrutinizing natural and synthetic derivatives for which chromones and their analogues were discovered to be a new and highly effective scaffold for the treatment of neglected diseases, including compounds with dual activity or activity against multiple parasites. Additionally, the efficacy of other new scaffolds was also thoroughly examined. This article also discusses prospects for identifying more unique targets for the disease, focusing on flavonoids as drug molecules that are less cytotoxic and high antiprotozoal potential. It also emphasizes the changes that can be made while searching for potential therapies-comparing existing treatments against protozoal diseases and the advantages of the newer chromone analogues over them. Finally, the structure- activity relationship at each atom of the chromone has also been highlighted.