Design, synthesis and biological evaluation of new class of pyrazoles-dihydropyrimidinone derivatives as bone anabolic agents.

This study explores a series of twenty-four newly synthesized pyrzole-dihydropyrimidinone hybrids as potential bone anabolic agents. Initially, an alkaline phosphatase assay, a common marker of bone formation, was used to screen all compounds for their ability to stimulate osteogenic potential. Initial screening identified three promising candidates (5f, 5u and 5w) that were subsequently confirmed to be non-toxic to osteoblasts.

Pym-18a, a novel pyrimidine derivative ameliorates glucocorticoid induced osteoblast apoptosis and promotes osteogenesis via autophagy and PINK 1/Parkin mediated mitophagy induction.

Glucocorticoid-induced osteoporosis (GIOP) is the most common type of secondary osteoporosis, marked by reduced bone density and impaired osteoblast function. Current treatments have serious side effects, highlighting the need for new drug candidates. Pyrimidine derivatives have been noted for their potential in suppressing osteoclastogenesis, but their effects on osteogenesis and GIOP remain underexplored.

Salmonella Typhimurium effector SseI regulates host peroxisomal dynamics to acquire lysosomal cholesterol.

Salmonella enterica serotype Typhimurium (Salmonella) resides and multiplies intracellularly in cholesterol-rich compartments called Salmonella-containing vacuoles (SCVs) with actin-rich tubular extensions known as Salmonella-induced filaments (SIFs). SCV maturation depends on host-derived cholesterol, but the transport mechanism of low-density lipoprotein (LDL)-derived cholesterol to SCVs remains unclear. Here we find that peroxisomes are recruited to SCVs and function as pro-bacterial organelle.

iDCNNPred: an interpretable deep learning model for virtual screening and identification of PI3Ka inhibitors against triple-negative breast cancer.

Triple-negative breast cancer (TNBC) lacks estrogen, progesterone, and HER2 expression, accounting for 15-20% of breast cancer cases. It is challenging due to low therapeutic response, heterogeneity, and aggressiveness. The PI3Ka isoform is a promising therapeutic target, often hyperactivated in TNBC, contributing to uncontrolled growth and cancer cell formation.

Pharmacophore-based 3D-QSAR modeling, virtual screening, docking, molecular dynamics and biological evaluation studies for identification of potential inhibitors of alpha-glucosidase.

Context: Alpha-glucosidase enzyme is considered an important therapeutic target for controlling hyperglycemia associated with type 2 diabetes. Novel scaffolds identified as potential alpha-glucosidase inhibitors from the Maybridge library utilizing pharmacophore modeling, molecular docking and biological evaluation are reported in this manuscript.

Method: A total of 51 xanthone series scaffolds previously reported as alpha-glucosidase inhibitors were collected and used as training and test sets.

ATM1, an essential conserved transporter in Apicomplexa, bridges mitochondrial and cytosolic [Fe-S] biogenesis.

The Apicomplexa phylum encompasses numerous obligate intracellular parasites, some associated with severe implications for human health, including Plasmodium, Cryptosporidium, and Toxoplasma gondii. The iron-sulfur cluster [Fe-S] biogenesis ISC pathway, localized within the mitochondrion or mitosome of these parasites, is vital for parasite survival and development. Previous work on T.

Molecular, structural, and functional characterization of delta subunit of T-complex protein-1 from .

Chaperonins/Heat shock protein 60 are ubiquitous multimeric protein complexes that assist in the folding of partially and/or misfolded proteins using metabolic energy into their native stage. The eukaryotic group II chaperonin, also referred as T-complex protein-1 ring complex (TRiC)/T-complex protein-1 (TCP1)/chaperonin containing T-complex protein (CCT), contains 8-9 paralogous subunits, arranged in each of the two rings of hetero-oligomeric complex. In , till date, only one subunit, LdTCP1γ, has been well studied.

Integrated machine learning-based virtual screening and biological evaluation for identification of potential inhibitors against cathepsin K.

Cathepsin K is a type of cysteine proteinase that is primarily expressed in osteoclasts and has a key role in the breakdown of bone matrix protein during bone resorption. Many studies suggest that the deficiency of cathepsin K is concomitant with a suppression of osteoclast functioning, therefore rendering the resorptive properties of cathepsin K the most prominent target for osteoporosis. This innovative work has identified a novel anti-osteoporotic agent against Cathepsin K by using a comparison of machine learning and deep learning-based virtual screening followed by their biological evaluation.

Exploring host epigenetic enzymes as targeted therapies for visceral leishmaniasis: in silico design and in vitro efficacy of KDM6B and ASH1L inhibitors.

In order to combat various infectious diseases, the utilization of host-directed therapies as an alternative to chemotherapy has gained a lot of attention in the recent past, since it bypasses the existing limitations of conventional therapies. The use of host epigenetic enzymes like histone lysine methyltransferases and lysine demethylases as potential drug targets has successfully been employed for controlling various inflammatory diseases like rheumatoid arthritis and acute leukemia. In our earlier study, we have already shown that the functional knockdown of KDM6B and ASH1L in the experimental model of visceral leishmaniasis has resulted in a significant reduction of organ parasite burden.

Synergy between human DNA ligase I and topoisomerase 1 unveils new therapeutic strategy for the management of colorectal cancer.

DNA topoisomerase 1 (Topo 1) is a pivotal player in various DNA processes, including replication, repair, and transcription. It serves as a target for anticancer drugs like camptothecin and its derivatives (Topotecan and SN-38/Irinotecan). However, the emergence of drug resistance and the associated adverse effects, such as alopecia, anemia, dyspnea, fever, chills, and painful or difficult urination, pose significant challenges in Topo 1-targeted therapy, necessitating urgent attention.

Metacaspase (Pf MCA-1) as antimalarial drug target: An in silico approach and their biological validation.

Aims: Acquired drug resistance of Plasmodium is a global issue for the treatment of malaria. There are various proteases in the genome of Plasmodium falciparum (P. falciparum) including metacaspase-1 (PfMCA-1) that are essential and are being considered as an attractive drug target.

Identification of potent inhibitors for homoserine kinase: an integrated and kinetic study.

Leishmaniasis is caused by ∼20 species of that affects millions in endemic areas. Available therapies are not sufficient to effectively control the disease, cause severe side effects and eventually lead to drug resistance, making the discovery of novel therapeutic molecules an immediate need. Molecular target-based drug discovery, where the target is a defined molecular gene, protein or a mechanism, is a rationale driven approach for novel therapeutics.

Identification of Potential Aldose Reductase Inhibitors Using Convolutional Neural Network-Based in Silico Screening.

Aldose reductase (ALR2) is a notable enzyme of the polyol pathway responsible for aggravating diabetic neuropathy complications. The first step begins when it catalyzes the reduction of glucose to sorbitol with NADPH as a coenzyme. Elevated concentrations of sorbitol damage the tissues, leading to complications like neuropathy.

Machine learning and biological evaluation-based identification of a potential MMP-9 inhibitor, effective against ovarian cancer cells SKOV3.

MMP-9, also known as gelatinase B, is a zinc-metalloproteinase family protein that plays a key role in the degradation of the extracellular matrix (ECM). The normal function of MMP-9 includes the breakdown of ECM, a process that aids in normal physiological processes such as embryonic development, angiogenesis, etc. Interruptions in these processes due to the over-expression or downregulation of MMP-9 are reported to cause some pathological conditions like neurodegenerative diseases and cancer.

Identification of novel TACE inhibitors using DNN based- virtual screening, molecular dynamics and biological evaluation.

Rheumatoid Arthritis (RA) is a well-known autoimmune inflammatory disease, distressing roughly 1% of the adult population throughout the globe. Many studies have suggested that overexpression of TNF-α, a pro-inflammatory cytokine, is responsible for the progression of RA. Furthermore, inhibition of the shedding rate of TNF-α is regulated by the TACE (TNF-α converting enzyme) protein and, hence is considered as an important therapeutic target for the prevention of progressive synovial joint destruction in rheumatoid arthritis.

Pancreastatin inhibitor PSTi8 ameliorates streptozotocin-induced diabetes by suppressing hepatic glucose production.

Elevated plasma glucose concentration, as a consequence of excessive hepatic glucose production, plays a pivotal role in the development of diabetes. A chromogranin A-derived diabetogenic peptide Pancreastatin (PST) enhances hepatic glucose output leading to diabetes. Therefore, here we probed the role of PSTi8, a PST inhibitor in ameliorating diabetes by investigating the effect of high glucose (HG) or PST on glucose metabolism.

Neohesperidin and spike RBD interaction in omicron and its sub-variants: In silico, structural and simulation studies.

COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged first around December 2019 in the city of Wuhan, China. Since then, several variants of the virus have emerged with different biological properties. This pandemic has so far led to widespread infection cycles with millions of fatalities and infections globally.

Artificial neural network models driven novel virtual screening workflow for the identification and biological evaluation of BACE1 inhibitors.

Beta-site amyloid-β precursor protein-cleaving enzyme 1 (BACE1) is a transmembrane aspartic protease and has shown potential as a possible therapeutic target for Alzheimer's disease. This aggravating disease involves the aberrant production of β amyloid plaques by BACE1 which catalyzes the rate-limiting step by cleaving the amyloid precursor protein (APP), generating the neurotoxic amyloid β protein that aggregates to form plaques leading to neurodegeneration. Therefore, it is indispensable to inhibit BACE1, thus modulating the APP processing.

An insight into the predictive interaction of Apolipoprotein-E with Epstein-Barr virus proteins and their probable role in mediating Alzheimer's disease.

Recent reports suggest that persistent Epstein-Barr virus (EBV) infection and its recurrent reactivation could instigate the formation of proteinaceous plaques in the brain: a hallmark of Alzheimer's disease (AD). Interestingly, a major genetic risk factor of AD, the apolipoprotein E (ApoE), could also influence the outcome of EBV infection in an individual. The ApoE is believed to influence the proteinaceous plaque clearance from the brain, and its defective functioning could result in the aggregate deposition.

Machine learning-based predictive modeling, virtual screening and biological evaluation studies for identification of potential inhibitors of MMP-13.

Matrix Metalloproteinase-13 (MMP-13) is a collagenase that regulates the homeostasis of the extracellular matrix (ECM) and basement membrane, as well as the breakdown of type II collagen. Recent research studies on the molecular and cellular mechanisms of cartilage degradation suggest that MMP-13 overexpression triggers osteoarthritis and is considered a promising target for osteoarthritis treatment. The present work employs machine learning-based virtual screening and structure-based rational drug design approaches to identify potential inhibitors of MMP-13 with diverse chemical scaffolds.

Design, synthesis and biological evaluation of (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives as inhibitors of Mycobacterium tuberculosis bd oxidase.

New chemical scaffolds with novel mechanism of action are urgently needed for the treatment of drug resistant tuberculosis. The oxidative phosphorylation pathway of Mycobacterium tuberculosis consists of multiple clinically validated drug targets. This pathway can function through any one of the two terminal oxidases-the proton pumping cytochrome bc-aa supercomplex, or the less energy efficient but high affinity cytochrome bd oxidase.

Ligand-based in silico identification and biological evaluation of potential inhibitors of nicotinamide N-methyltransferase.

Nicotinamide N-methyltransferase (NNMT) is a protein coding gene, which methylates the nicotinamide (NA) (vitamin B3) to produce 1-methylnicotinamide (MNA). Several studies have suggested that the overexpression of NNMT is associated with different metabolic disorders like obesity and type-2 diabetes thereby making it an important therapeutic target for development of anti-diabetic agents. Here we describe a workflow for identification of new inhibitors of NNMT from a library of small molecules.

Adiponectin receptors by increasing mitochondrial biogenesis and respiration promote osteoblast differentiation: Discovery of isovitexin as a new class of small molecule adiponectin receptor modulator with potential osteoanabolic function.

Previously, we established adiponectin receptors (AdipoRs) as osteoanabolic target. To discover small molecule agonists of AdipoRs, we studied apigenin and apigenin-6C-glucopyranose (isovitexin) that induced osteoblast differentiation. In-silico, in vitro and omics-based studies were performed.