Novel pyrrolone-fused benzosuberene MK2 inhibitors: synthesis, pharmacophore modelling, molecular docking, and anti-cancer efficacy evaluation in HNSCC cells.

Head and neck Squamous Cell Carcinoma (HNSCC) is a growing concern worldwide and MAPKAPK2/MK2 (Mitogen-Activated Protein Kinase Activated Protein Kinase 2) is crucially involved in HNSCC progression. Increased disease burden and lacuna of targeted therapies require novel and safe pharmacological inhibitors to suppress the well-explored molecular targets in HNSCC. Here, we used dibromo-substituted benzosuberene synthesized from the mixture of α, β, γ-himachalenes and utilized as a precursor for the synthesis of Pyrrolone-fused benzosuberenes (PfBS) as MK2 inhibitors through aminocarbonylation approach in a single-pot reaction.

Computational and experimental analysis of Luteolin-β-cyclodextrin supramolecular complexes: Insights into conformational dynamics and phase solubility.

Investigating the structural stability of poorly-soluble luteolin (LuT) after encapsulation within cyclodextrins (CDs) is crucial for unlocking the therapeutic potential of LuT bioactive molecule. Herein, native and modified β-CD were employed to investigate LuT inclusion complex formation. Molecular mechanics (MM) and quantum mechanics (QM) were utilized for structural dynamics analysis.

Highly robust quantum mechanics and umbrella sampling studies on inclusion complexes of curcumin and β-cyclodextrin.

The poor aqueous solubility of curcumin (CUR) obstructs its wide utilization in nutraceuticals, cosmetics, and pharmaceutical companies. This study is dedicated to investigate the stability of CUR inside the hydrophobic pocket of β-cyclodextrin (β-CD), hydroxypropyl-β-CD (HP-β-CD), and 2,6-Di-O-methyl-β-CD (DM-β-CD). Initially, molecular mechanics (MM) calculations and subsequently quantum mechanical (QM) calculations were performed on inclusion complexes to strengthen the MM results.

Dispersion-corrected DFT calculations and umbrella sampling simulations to investigate stability of Chrysin-cyclodextrin inclusion complexes.

The study of inclusion complexes of Chrysin (ChR) with three forms of cyclodextrins (CDs) α-, β-, and γ-CD was accomplished to examine the stability of ChR inside the central cavities of CDs. The aim of study was to identify the most suitable form of CD to improve the hydro-solubility of poorly soluble ChR bioactive molecule. Microsecond timescale molecular dynamics (MD) simulations were performed on four inclusion complexes (α-CD/ChR, β-CD/ChR, and two conformations of γ-CD/ChR) to examine the dynamics of ChR inside the cavity of CDs.

A comparative study on inclusion complex formation between formononetin and β-cyclodextrin derivatives through multiscale classical and umbrella sampling simulations.

Formononetin, a naturally occurring isoflavone exhibits a wide range of therapeutic applications including antioxidant, anti-tumor, antiviral, anti-diabetic and neuroprotective activities. However, the low hydro-solubility of formononetin has limited its prospective use in cosmetic, neutraceutical and pharmaceutical industries. Cyclodextrins (CDs), especially β-CD and its derivatives have emerged as promising agents to improve the water solubility of poorly hydrosoluble compounds by the formation of inclusion complexes.

Structure restoration and aggregate inhibition of V30M mutant transthyretin protein by potential quinoline molecules.

Transthyretin (TTR) is a tetrameric protein found in human plasma and cerebrospinal fluid that functions as a transporter of thyroxine (T4) and retinol. A mutation resulting in the substitution of valine to methionine at position 30 (V30M) is the most common mutation that destabilizes the tetramer structure of TTR protein resulting in a fatal neuropathy known as TTR amyloidosis. The V30M TTR-induced neuropathy can be inhibited through stabilization of the TTR tetramer by the binding of small molecules.

Inhibition of nonstructural protein 15 of SARS-CoV-2 by golden spice: A computational insight.

The quick widespread of the coronavirus and speedy upsurge in the tally of cases demand the fast development of effective drugs. The uridine-directed endoribonuclease activity of nonstructural protein 15 (Nsp15) of the coronavirus is responsible for the invasion of the host immune system. Therefore, developing potential inhibitors against Nsp15 is a promising strategy.

Theaflavin 3-gallate inhibits the main protease (M) of SARS-CoV-2 and reduces its count in vitro.

The main protease (M) of SARS-CoV-2 has been recognized as an attractive drug target because of its central role in viral replication. Our previous preliminary molecular docking studies showed that theaflavin 3-gallate (a natural bioactive molecule derived from theaflavin and found in high abundance in black tea) exhibited better docking scores than repurposed drugs (Atazanavir, Darunavir, Lopinavir). In this study, conventional and steered MD-simulations analyses revealed stronger interactions of theaflavin 3-gallate with the active site residues of M than theaflavin and a standard molecule GC373 (a known inhibitor of M and novel broad-spectrum anti-viral agent).

A ricin-based peptide BRIP from Hordeum vulgare inhibits M of SARS-CoV-2.

COVID-19 pandemic caused by SARS-CoV-2 led to the research aiming to find the inhibitors of this virus. Towards this world problem, an attempt was made to identify SARS-CoV-2 main protease (M) inhibitory peptides from ricin domains. The ricin-based peptide from barley (BRIP) was able to inhibit M in vitro with an IC of 0.

Computational targeting of allosteric site of MEK1 by quinoline-based molecules.

MEK1 is an attractive target due to its role in selective extracellular-signal-regulated kinase phosphorylation, which plays a pivotal role in regulating cell proliferation. Another benefit of targeting the MEK protein is its unique hydrophobic pocket that can accommodate highly selective allosteric inhibitors. To date, various MEK1 inhibitors have reached clinical trials against several cancers, but they were discarded due to their severe toxicity and low efficacy.

Benchmarking the ability of novel compounds to inhibit SARS-CoV-2 main protease using steered molecular dynamics simulations.

Background: The SARS-CoV-2 main protease (M) is an attractive target in the COVID-19 drug development process. It catalyzes the polyprotein's translation from viral RNA and specifies a particular cleavage site. Due to the absence of identical cleavage specificity in human cell proteases, targeting M with chemical compounds can obstruct the replication of the virus.

A lesson for the maestro of the replication fork: Targeting the protein-binding interface of proliferating cell nuclear antigen for anticancer therapy.

The proliferating cell nuclear antigen (PCNA) has emerged as a promising candidate for the development of novel cancer therapeutics. PCNA is a nononcogenic mediator of DNA replication that regulates a diverse range of cellular functions and pathways through a comprehensive list of protein-protein interactions. The hydrophobic binding pocket on PCNA offers an opportunity for the development of inhibitors to target various types of cancers and modulate protein-protein interactions.

Identification of 11β-HSD1 inhibitors through enhanced sampling methods.

Aminoarylbenzosuberene (AAB) molecules were chosen for analysis to develop effective and more competent 11β-hydroxysteroid dehydrogenase (11β-HSD1) protein inhibitors. The AAB4 molecule was shown to have stronger interactions and binding affinity than standard inhibitors (co-crystallized molecules). These results were based on conventional, steered and enhanced umbrella sampling simulations.

Identification of acridinedione scaffolds as potential inhibitor of DENV-2 C protein: An in silico strategy to combat dengue.

Dengue is a prominent viral disease transmitted by mosquitoes to humans that affects mainly tropical and subtropical countries worldwide. The global spread of dengue virus (DENV) is mainly occurred by Aedes aegypti and Aedes albopictus mosquitoes. The dengue virus serotypes-2 (DENV-2) is a widely prevalent serotype of DENV, that causes the hemorrhagic fever and bleeding in the mucosa, which can be fatal.

Mechanistic behavior and subtle key events during DNA clamp opening and closing in T4 bacteriophage.

Clamp loaders ensure processive DNA replication by loading the toroidal shaped sliding clamps onto the DNA. The sliding clamps serve as a platform for the attachment of polymerases and several other proteins associated with the regulation of various cellular processes. Clamp loaders are fascinating as nanomachines that engage in protein-protein and protein-DNA interactions.

Potential of turmeric-derived compounds against RNA-dependent RNA polymerase of SARS-CoV-2: An in-silico approach.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of the COVID-19 pandemic. Currently, there are no particular antivirals available to battle with COVID-19. The RNA-dependent RNA polymerase (RdRp) has emerged as a novel drug target due to its essential role in virus replication.

Site-directed mutagenesis (P61G) of copper, zinc superoxide dismutase enhances its kinetic properties and tolerance to inactivation by HO.

Superoxide dismutases (SODs) protect the cells by catalyzing the dismutation of harmful superoxide radicals (O) into molecular oxygen (O) and hydrogen peroxide (HO). Here, a Cu, Zn SOD (WT) from a high altitude plant (Potentilla atrosanguinea) was engineered by substituting a conserved residue proline to glycine at position 61 (P61G). The computational analysis showed higher structural flexibility and clusters in P61G than WT.

Improving the catalytic efficiency and dimeric stability of Cu,Zn superoxide dismutase by combining structure-guided consensus approach with site-directed mutagenesis.

Superoxide dismutase (SOD) leads the front line of defense against injuries mediated by the reactive oxygen species (ROS). The SOD from a high-altitude plant Potentilla atrosanguinea is a unique thermostable enzyme. In this study, we applied a structure-guided consensus approach on Cu,Zn SOD from Potentilla atrosanguinea plant, to improve its enzymatic properties.

Identification of potential plant bioactive as SARS-CoV-2 Spike protein and human ACE2 fusion inhibitors.

The Spike receptor binding domain (S-RBD) from SARS-CoV-2, a crucial protein for the entrance of the virus into target cells is known to cause infection by binding to a cell surface protein. Hence, reckoning therapeutics for the S-RBD of SARS-CoV-2 may address a significant way to target viral entry into the host cells. Herein, through in-silico approaches (Molecular docking, molecular dynamics (MD) simulations, and end-state thermodynamics), we aimed to screen natural molecules from different plants for their ability to inhibit S-RBD of SARS-CoV-2.

A computational approach for rational discovery of inhibitors for non-structural protein 1 of SARS-CoV-2.

Background: Non-structural protein 1 (Nsp1), a virulence agent of SARS-CoV-2, has emerged as an important target for drug discovery. Nsp1 shuts down the host gene function by associating with the 40S ribosomal subunit.

Methods: Molecular interactions, drug-likeness, physiochemical property predictions, and robust molecular dynamics (MD) simulations were employed to discover novel Nsp1 inhibitors.

Bioactive Molecules of Tea as Potential Inhibitors for RNA-Dependent RNA Polymerase of SARS-CoV-2.

The coronavirus disease (COVID-19), a worldwide pandemic, is caused by the severe acute respiratory syndrome-corona virus-2 (SARS-CoV-2). At this moment in time, there are no specific therapeutics available to combat COVID-19. Drug repurposing and identification of naturally available bioactive molecules to target SARS-CoV-2 are among the key strategies to tackle the notorious virus.

In-silico evaluation of bioactive compounds from tea as potential SARS-CoV-2 nonstructural protein 16 inhibitors.

Background And Aim: A novel coronavirus, called the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been found to cause COVID-19 in humans and some other mammals. The nonstructural protein 16 (NSP16) of SARS-CoV-2 plays a significant part in the replication of viruses and suppresses the ability of innate immune system to detect the virus. Therefore, inhibiting NSP16 can be a secure path towards identifying a potent medication against SARS-CoV-2.

Plant-based analogues identified as potential inhibitor against tobacco mosaic virus: A biosimulation approach.

Benzosuberene compounds with a pyrrolone group adhered to it are compounds extracted from the oils of Cedrus deodara plant, that bear inhibitory capabilities. Tobacco mosaic virus is known to affect crop production every year. The currently known inhibitors against TMV have a weak inhibition effect and also tend to be toxic towards non-target living organisms as well as the environment.

Identification of selective cyclin-dependent kinase 2 inhibitor from the library of pyrrolone-fused benzosuberene compounds: an in silico exploration.

The over-expression of cyclin-dependent kinase 2 is related to multiple cancers, which has led them to be a widely researched topic for nearly two decades. The prime focus of the present research is to design new potent and specific inhibitors against CDK2 to suppress cancer cell proliferation. In this study, we have chosen Flavopiridol, SU9516, and CVT-313 as standard inhibitors to compare with in-house synthesized pyrrolone-fused benzosuberene (PBS) compounds.

Evaluation of acridinedione analogs as potential SARS-CoV-2 main protease inhibitors and their comparison with repurposed anti-viral drugs.

Background: The main protease (Mpro) of SARS-CoV-2 is involved in the processing of vital polypeptides required for viral genome replication and transcription and is one of the best-characterized targets to inhibit the progression of SARS-CoV-2 in infected individuals.

Methods: We screened a set of novel classes of acridinediones molecules to efficiently bind and inhibit the activity of the SARS-CoV-2 by targeting the Mpro. The repurposed FDA-approved antivirals were taken as standard molecules for this study.