Pharmacological Profile of Novel Anti-cancer Drugs Approved by USFDA in 2022: A Review.

Background: For any drug molecule, it is mandatory to pass the drug approval process of the concerned regulatory authority, before being marketed. The Food and Drug Administration (FDA), throughout the year, approves several new drugs for safety and efficacy. In addition to new drug approvals, FDA also works on improving access to generic drugs, aimed to lower the cost of drugs for patients and improve access to treatments.

Mechanistic insights into global suppressors of protein folding defects.

Most amino acid substitutions in a protein either lead to partial loss-of-function or are near neutral. Several studies have shown the existence of second-site mutations that can rescue defects caused by diverse loss-of-function mutations. Such global suppressor mutations are key drivers of protein evolution.

A Systematic Review of Updated Mechanistic Insights Towards Alzheimer's Disease.

Background: Alzheimer's disease (AD) is a degenerative neurological disorder that impairs memory, cognitive abilities, and the ability to do everyday activities. This neurodegenerative disease is growing increasingly common as the world's population ages. Here, we reviewed some of the key findings showing the function of Aβ peptide, oxidative stress, free radical damage Triggering Receptors Expressed cn Myeloid Cells 2 (TREM2), Nitric Oxide (NO) and gut microbiota in the aetiology of AD.

Bioisosteres of Indomethacin as Inhibitors of Aldo-Keto Reductase 1C3.

Aldo-keto reductase 1C3 (AKR1C3) is an attractive target in drug design for its role in resistance to anticancer therapy. Several nonsteroidal anti-inflammatory drugs such as indomethacin are known to inhibit AKR1C3 in a nonselective manner because of COX-off target effects. Here we designed two indomethacin analogues by proposing a bioisosteric connection between the indomethacin carboxylic acid function and either hydroxyfurazan or hydroxy triazole rings.

Hydroxyazole scaffold-based Plasmodium falciparum dihydroorotate dehydrogenase inhibitors: Synthesis, biological evaluation and X-ray structural studies.

Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) has been clinically validated as a target for antimalarial drug discovery, as a triazolopyrimidine class inhibitor (DSM265) is currently undergoing clinical development. Here, we have identified new hydroxyazole scaffold-based PfDHODH inhibitors belonging to two different chemical series. The first series was designed by a scaffold hopping strategy that exploits the use of hydroxylated azoles.

Targeting Myeloid Differentiation Using Potent 2-Hydroxypyrazolo[1,5- a]pyridine Scaffold-Based Human Dihydroorotate Dehydrogenase Inhibitors.

Human dihydroorotate dehydrogenase ( hDHODH) catalyzes the rate-limiting step in de novo pyrimidine biosynthesis, the conversion of dihydroorotate to orotate. hDHODH has recently been found to be associated with acute myelogenous leukemia, a disease for which the standard of intensive care has not changed over decades. This work presents a novel class of hDHODH inhibitors, which are based on an unusual carboxylic group bioisostere 2-hydroxypyrazolo[1,5- a]pyridine, that has been designed starting from brequinar, one of the most potent hDHODH inhibitors.

Substrate-bound outward-open structure of a Na-coupled sialic acid symporter reveals a new Na site.

Many pathogenic bacteria utilise sialic acids as an energy source or use them as an external coating to evade immune detection. As such, bacteria that colonise sialylated environments deploy specific transporters to mediate import of scavenged sialic acids. Here, we report a substrate-bound 1.

Potent and selective aldo-keto reductase 1C3 (AKR1C3) inhibitors based on the benzoisoxazole moiety: application of a bioisosteric scaffold hopping approach to flufenamic acid.

The aldo-keto reductase 1C3 (AKR1C3) isoform plays a vital role in the biosynthesis of androgens and is considered an attractive target in prostate cancer (PCa). No AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid and indomethacine are non-steroidal anti-inflammatory drugs known to inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed.

"Just a spoonful of sugar...": import of sialic acid across bacterial cell membranes.

Eukaryotic cell surfaces are decorated with a complex array of glycoconjugates that are usually capped with sialic acids, a large family of over 50 structurally distinct nine-carbon amino sugars, the most common member of which is N-acetylneuraminic acid. Once made available through the action of neuraminidases, bacterial pathogens and commensals utilise host-derived sialic acid by degrading it for energy or repurposing the sialic acid onto their own cell surface to camouflage the bacterium from the immune system. A functional sialic acid transporter has been shown to be essential for the uptake of sialic acid in a range of human bacterial pathogens and important for host colonisation and persistence.

Antiurolithiatic Potential of Neeri against Calcium-Oxalate Stones by Crystallization Inhibition, Free Radicals Scavenging, and NRK-52E Cell Protection from Oxalate Injury.

Background: Neeri is a well-established polyherbal formulation prescribed for renal stones by the physicians but has not been experimentally evaluated for its antiurolithiatic potential using cell-lines.

Objective: This study is aimed to scientifically substantiate the antiurolithiatic effect of Neeri extract (NRE) through calcium oxalate (CaOx) crystallization inhibition, scavenging of free radicals, and protection of renal tubular epithelial NRK-52E cells from oxalate-induced injury.

Materials And Methods: The crystallization inhibition was studied by turbidimetric assay while the free radical scavenging potential was determined for superoxide and nitric oxide (NO) radicals.

Crystal structure of N-acetylmannosamine kinase from Fusobacterium nucleatum.

Sialic acids comprise a varied group of nine-carbon amino sugars that are widely distributed among mammals and higher metazoans. Some human commensals and bacterial pathogens can scavenge sialic acids from their environment and degrade them for use as a carbon and nitrogen source. The enzyme N-acetylmannosamine kinase (NanK; EC 2.

Design, synthesis, biological evaluation and X-ray structural studies of potent human dihydroorotate dehydrogenase inhibitors based on hydroxylated azole scaffolds.

A new generation of potent hDHODH inhibitors designed by a scaffold-hopping replacement of the quinolinecarboxylate moiety of brequinar, one of the most potent known hDHODH inhibitors, is presented here. Their general structure is characterized by a biphenyl moiety joined through an amide bridge with an acidic hydroxyazole scaffold (hydroxylated thiadiazole, pyrazole and triazole). Molecular modelling suggested that these structures should adopt a brequinar-like binding mode involving interactions with subsites 1, 2 and 4 of the hDHODH binding site.

Multiple enzymatic activities of ParB/Srx superfamily mediate sexual conflict among conjugative plasmids.

Conjugative plasmids are typically locked in intergenomic and sexual conflicts with co-resident rivals, whose translocation they block using fertility inhibition factors (FINs). We describe here the first crystal structure of an enigmatic FIN Osa deployed by the proteobacterial plasmid pSa. Osa contains a catalytically active version of the ParB/Sulfiredoxin fold with both ATPase and DNase activity, the latter being regulated by an ATP-dependent switch.

Structural and mechanistic insights into the bacterial amyloid secretion channel CsgG.

Curli are functional amyloid fibres that constitute the major protein component of the extracellular matrix in pellicle biofilms formed by Bacteroidetes and Proteobacteria (predominantly of the α and γ classes). They provide a fitness advantage in pathogenic strains and induce a strong pro-inflammatory response during bacteraemia. Curli formation requires a dedicated protein secretion machinery comprising the outer membrane lipoprotein CsgG and two soluble accessory proteins, CsgE and CsgF.

Secretion and functional display of fusion proteins through the curli biogenesis pathway.

Curli are functional amyloids expressed as fibres on the surface of Enterobacteriaceae. Contrary to the protein misfolding events associated with pathogenic amyloidosis, curli are the result of a dedicated biosynthetic pathway. A specialized transporter in the outer membrane, CsgG, operates in conjunction with the two accessory proteins CsgE and CsgF to secrete curlin subunits to the extracellular surface, where they nucleate into cross-beta strand fibres.

Crystallization and preliminary X-ray crystallographic analysis of the curli transporter CsgG.

Gram-negative bacteria have eight known protein secretion systems. The type-VIII secretion system, also known as the curli biosynthesis system, is responsible for the formation of aggregative fibres known in Escherichia coli as curli. Curli are extracellular proteinaceous fibres primarily involved in bacterial biofilm formation and attachment to nonbiotic surfaces.

The mannose-specific lectin domains of Flo1p from Saccharomyces cerevisiae and Lg-Flo1p from S. pastorianus: crystallization and preliminary X-ray diffraction analysis of the adhesin-carbohydrate complexes.

Flo1p and Lg-Flo1p are two cell-wall adhesins belonging to the Flo (flocculation) protein family from the yeasts Saccharomyces cerevisiae and S. pastorianus. The main function of these modular proteins endowed with calcium-dependent lectin activity is to mediate cell-cell adhesion events during yeast flocculation, a process which is well known at the cellular level but still not fully characterized from a molecular perspective.

Inhibition of MAO and GABA: probable mechanisms for antidepressant-like activity of Nardostachys jatamansi DC. in mice.

Ethanolic extract (100, 200 and 400 mg/kg, po) of N. jatamansi administered for 14 successive days to Swiss young albino mice (either sex) produced significant antidepressant-like effect in both tail suspension and forced swim tests. The efficacy of the extract was found to be comparable to imipramine (15 mg/kg, po) and sertraline (20 mg/kg, po).

Liposomal drug delivery systems--clinical applications.

Liposomes have been widely investigated since 1970 as drug carriers for improving the delivery of therapeutic agents to specific sites in the body. As a result, numerous improvements have been made, thus making this technology potentially useful for the treatment of certain diseases in the clinics. The success of liposomes as drug carriers has been reflected in a number of liposome-based formulations, which are commercially available or are currently undergoing clinical trials.