Identification of novel allosteric sites of SARS-CoV-2 papain-like protease (PLpro) for the development of COVID-19 antivirals.

Coronaviruses such as SARS-CoV-2 encode a conserved papain-like protease (PLpro) that is crucial for viral replication and immune evasion, making it a prime target for antiviral drug development. In this study, three surface pockets on SARS-CoV-2 PLpro that may function as sites for allosteric inhibition were computationally identified. To evaluate the effects of these pockets on proteolytic activity, 52 residues were separately mutated to alanine.

Cellular and functional evaluation of LDLR missense variants reported in hypercholesterolemic patients demonstrates their hypomorphic impacts on trafficking and LDL internalization.

Background: Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by increased LDL-cholesterol levels. About 85% of FH cases are caused by mutations encoding the low-density lipoprotein receptor (LDLR). LDLR is synthesized in the endoplasmic reticulum (ER) where it undergoes post-translational modifications and then transported through Golgi apparatus to the plasma membrane.

Boosting the Accuracy and Chemical Space Coverage of the Detection of Small Colloidal Aggregating Molecules Using the BAD Molecule Filter.

The ability to conduct effective high throughput screening (HTS) campaigns in drug discovery is often hampered by the detection of false positives in these assays due to small colloidally aggregating molecules (SCAMs). SCAMs can produce artifactual hits in HTS by nonspecific inhibition of the protein target. In this work, we present a new computational prediction tool for detecting SCAMs based on their 2D chemical structure.

Molecular dynamics simulations as a guide for modulating small molecule aggregation.

Small colloidally aggregating molecules (SCAMs) can be problematic for biological assays in drug discovery campaigns. However, the self-associating properties of SCAMs have potential applications in drug delivery and analytical biochemistry. Consequently, the ability to predict the aggregation propensity of a small organic molecule is of considerable interest.

Novel Thiazolidinedione and Rhodanine Derivatives Regulate Glucose Metabolism, Improve Insulin Sensitivity, and Activate the Peroxisome Proliferator-Activated γ Receptor.

Sixteen novel thiazolidinedione (TZD) and rhodanine (RD) derivatives were designed and synthesized by introducing a pyrimidine moiety at different sites of pioglitazone's structure. The effects of synthesized compounds on regulating glucose metabolism, improving insulin sensitivity, and activating the peroxisome proliferator-activated γ receptor (PPAR-γ) were evaluated in βTC6 cells. Compounds TZDs # , , , and reduced the basal insulin secretion by ∼20.

Discovery of pyrimidoindol and benzylpyrrolyl inhibitors targeting SARS-CoV-2 main protease (M) through pharmacophore modelling, covalent docking, and biological evaluation.

The main protease (M) enzyme has an imperative function in disease progression and the life cycle of the SARS-CoV-2 virus. Although the orally active drug nirmatrelvir (co-administered with ritonavir as paxlovid) has been approved for emergency use as the frontline antiviral agent, there are a number of limitations that necessitate the discovery of new drug scaffolds, such as poor pharmacokinetics and susceptibility to proteolytic degradation due to its peptidomimetic nature. This study utilized a novel virtual screening workflow that combines pharmacophore modelling, multiple-receptor covalent docking, and biological evaluation in order to find new M inhibitors.

The Discovery of Novel Small Oxindole-Based Inhibitors Targeting the SARS-CoV-2 Main Protease (M ).

With the potential for coronaviruses to re-emerge and trigger future pandemics, the urgent development of antiviral inhibitors against SARS-CoV-2 is essential. The M enzyme is crucial for disease progression and the virus's life cycle. It possesses allosteric sites that can hinder its catalytic activity, with some of these sites located at or near the dimerization interface.

Novel compound heterozygous variants (c.971delA/c.542C > T) in causes spastic tetraplegia, thin corpus callosum, and progressive microcephaly: a case report and mutational analysis.

Spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM) are linked to genetic variants since the first reported case in 2015. encodes for the neutral amino acid transporter ASCT1 which is involved in the transportation of serine between astrocytes and neurons. Although most of the reported cases are of Ashkenazi Jewish ancestry, SPATCCM has also been reported in Irish, Italian, Czech, Palestinian, and Pakistani ethnicities.

Molecular Modelling Study and Antibacterial Evaluation of Diphenylmethane Derivatives as Potential FabI Inhibitors.

The need for new antibiotics has become a major worldwide challenge as bacterial strains keep developing resistance to the existing drugs at an alarming rate. Enoyl-acyl carrier protein reductases (FabI) play a crucial role in lipids and fatty acid biosynthesis, which are essential for the integrity of the bacterial cell membrane. Our study aimed to discover small FabI inhibitors in continuation to our previously found hit MN02.

Are we ready yet for digital transformation? Virtual versus on-campus OSCE as assessment tools in pharmacy education. A randomized controlled head-to-head comparative assessment.

Background: The global COVID-19 pandemic has influenced pharmacy education including learning, assessment, and exams. In the UAE, pharmacy instructors have adapted several innovative teaching methods to strive for quality learning outcomes. The current trial presented a head-to-head comparative assessment between on-campus versus virtual Objective Structured Clinical Examination (OSCE) with examiners' and students' perspectives.

GW-2974 and SCH-442416 modulators of tyrosine kinase and adenosine receptors can also stabilize human telomeric G-quadruplex DNA.

GW-2974 is a potent tyrosine kinase receptor inhibitor while SCH-442416 is a potent adenosine receptors' antagonist with high selectivity towards human adenosine A2A receptor over other adenosine receptors. The two compounds were reported to possess anti-cancer properties. This study aimed to investigate whether stabilization of human telomeric G-quadruplex DNA by GW-2974- and SCH-442416 is a plausible fundamental mechanism underlying their anti-cancer effects.

The Discovery of Small Allosteric and Active Site Inhibitors of the SARS-CoV-2 Main Protease via Structure-Based Virtual Screening and Biological Evaluation.

The main protease enzyme (M) of SARS-CoV-2 is one of the most promising targets for COVID-19 treatment. Accordingly, in this work, a structure-based virtual screening of 3.8 million ligand libraries was carried out.

Allosteric Binding Sites of the SARS-CoV-2 Main Protease: Potential Targets for Broad-Spectrum Anti-Coronavirus Agents.

The current pandemic caused by the COVID-19 disease has reached everywhere in the world and has affected every aspect of our lives. As of the current data, the World Health Organization (WHO) has reported more than 300 million confirmed COVID-19 cases worldwide and more than 5 million deaths. M is an enzyme that plays a key role in the life cycle of the SARS-CoV-2 virus, and it is vital for the disease progression.

Structure-based assessment and druggability classification of protein-protein interaction sites.

The featureless interface formed by protein-protein interactions (PPIs) is notorious for being considered a difficult and poorly druggable target. However, recent advances have shown PPIs to be druggable, with the discovery of potent inhibitors and stabilizers, some of which are currently being clinically tested and approved for medical use. In this study, we assess the druggability of 12 commonly targeted PPIs using the computational tool, SiteMap.

The Discovery of Potent SHP2 Inhibitors with Anti-Proliferative Activity in Breast Cancer Cell Lines.

Despite available treatments, breast cancer is the leading cause of cancer-related death. Knowing that the tyrosine phosphatase SHP2 is a regulator in tumorigenesis, developing inhibitors of SHP2 in breast cells is crucial. Our study investigated the effects of new compounds, purchased from NSC, on the phosphatase activity of SHP2 and the modulation of breast cancer cell lines' proliferation and viability.

Computer-aided approaches reveal trihydroxychroman and pyrazolone derivatives as potential inhibitors of SARS-CoV-2 virus main protease.

COVID-19 was declared a pandemic by the World Health Organization (WHO) in March 2020. The disease is caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV-2). The aim of this study is to target the SARS-CoV-2 virus main protease (M) structure-based virtual screening.

Controlled Release of Pyrimidine Compound Using Polymeric Coated ZIF-8 Metal-Organic Framework as Glucagon-Like Peptide-1 Receptor Agonist Carrier.

This work demonstrates synthetic strategies for the incorporation of a synthesized pyrimidine glucagon-like peptide-1 (GLP-1) agonist into alginate-coated ZIF-8. The prepared pyrimidine GLP-1 agonist used for the treatment of diabetes type II, was trapped inside polymer coated ZIF-8. The encapsulation of the GLP-1 agonist was confirmed by UV-visible and FT-IR spectroscopies.

How Do Small Molecule Aggregates Inhibit Enzyme Activity? A Molecular Dynamics Study.

Small molecule compounds which form colloidal aggregates in solution are problematic in early drug discovery; adsorption of the target protein by these aggregates can lead to false positives in inhibition assays. In this work, we probe the molecular basis of this inhibitory mechanism using molecular dynamics simulations. Specifically, we examine in aqueous solution the adsorption of the enzymes β-lactamase and PTP1B onto aggregates of the drug miconazole.

The pharmacological chaperone N-n-butyl-deoxygalactonojirimycin enhances β-galactosidase processing and activity in fibroblasts of a patient with infantile GM1-gangliosidosis.

GM1-gangliosidosis, a lysosomal storage disorder, is associated with ~ 161 missense variants in the GLB1 gene. Affected patients present with β-galactosidase (β-Gal) deficiency in lysosomes. Loss of function in ER-retained misfolded enzymes with missense variants is often due to subcellular mislocalization.

Investigation of New Inhibitors of UDP-N-Acetylglucosamine Enolpyruvyl Transferase (MurA) by Virtual Screening with Antibacterial Assessment.

Background: Considering the interesting role in the peptidoglycan biosynthesis pathway, the enzyme UDP-N-acetylglucosamine enolpyruvyl transferase is an attractive target to develop new antibacterial agents. It catalyzes the first key step of this pathway and its inhibition leads to bacterial cell death. Fosfomycin is known as the natural inhibitor of MurA.

Characterization of human serum albumin's interactions with safranal and crocin using multi-spectroscopic and molecular docking techniques.

Interaction mechanisms of human serum albumin (HSA) with safranal and crocin were studied using UV-Vis absorption, fluorescence quenching and circular dichroism (CD) spectroscopies as well as molecular docking techniques. Changes in absorbance and fluorescence of HSA upon interactions with both compounds were attributed to their binding to amino acid chromophores located in subdomains IIA and IIIA. Fluorescence secondary inner filter effect was excluded using 278 nm and 340 nm as the wavelengths of HSA's excitation and fluorescence while safranal and crocin absorbed at 320 nm and 445 nm, respectively.

A Novel Homozygous Missense Variant in the NAGA Gene with Extreme Intrafamilial Phenotypic Heterogeneity.

Schindler disease is a rare autosomal recessive lysosomal storage disorder caused by a deficiency in alpha-N-acetylgalactosaminidase (α-NAGA) activity due to defects in the NAGA gene. Accumulation of the enzyme's substrates results in clinically heterogeneous symptoms ranging from asymptomatic individuals to individuals with severe neurological manifestations. Here, a 5-year-old Emirati male born to consanguineous parents presented with congenital microcephaly and severe neurological manifestations.

Discovery of new butyrylcholinesterase inhibitors via structure-based virtual screening.

Butyrylcholinesterase (BChE) plays an important role in the progression of the Alzheimer's disease. In this study, we used a structure-based virtual screening (VS) approach to discover new BChE inhibitors. A ligand database was filtered and docked to the BChE protein using Glide program.

Molecular modelling studies on ɑ7 nicotinic receptor allosteric modulators yields novel filter-based virtual screening protocol.

The ɑ7 receptor is a member in the nicotinic acetylcholine receptor (nAChR) which has been implicated in several neurological disorders. Beside normal agonists and antagonists of α7 nAChRs, several studies revealed other types of molecules that are able to activate or deactivate ɑ7 receptors via allosteric binding; those are called positive allosteric modulators (PAMs) or negative allosteric modulators (NAMs), with the former having more pharmacological importance than the latter. Since both types of modulators are believed to bind to the same place in the intracavity of the transmembrane domain, it was important to differentiate between them in terms of structural features and their binding with the target receptor, and then use these specific characteristics as filters to discriminate PAMs from NAMS.