Discovery of a Chimeric Polyketide Family as Cancer Immunogenic Chemotherapeutic Leads.

Discovery of cancer immunogenic chemotherapeutics represents an emerging, highly promising direction for cancer treatment that uses a chemical drug to achieve the efficacy of both chemotherapy and immunotherapy. Herein, we report a high-throughput screening platform and the subsequent discovery of a new class of cancer immunogenic chemotherapeutic leads. Our platform integrates informatics-based activity metabolomics for the rapid identification of microbial natural products with both novel structures and potent activities.

Unbiased Drug Target Prediction Reveals Sensitivity to Ferroptosis Inducers, HDAC and RTK Inhibitors in Melanoma Subtypes.

Background: The utilization of PD1 and CTLA4 inhibitors has revolutionized the treatment of malignant melanoma (MM). However, resistance to targeted and immune-checkpoint-based therapies still poses a significant problem.

Objective: Here, we mine large-scale MM proteogenomic data to identify druggable targets and forecast treatment efficacy and resistance.

Generating a Peptide Library Using the Repeats of Amino Acid Scaffolds Created by Sliding the Framework of a 7-mer Human Chemerin Segment and Discovery of Potent Antibacterial and Antimycobacterial Peptides.

The quest for new approaches for generating novel bioactive designer proteins/peptides has continued with their success in various biomedical applications. Previously, we designed a 14-mer α-helical peptide with antimicrobial and antimycobacterial activities by employing a tandem repeat of the 7-mer, "KVLGRLV" human chemerin segment. Herein, we devised a new method of "sliding framework" with this segment to create amino acid scaffolds of varying sizes and sequences and explored the design of a peptide library with antibacterial and antimycobacterial activities.

Design, Synthesis, and Evaluation of Novel 2,4-disubstituted Pyrimidine Derivatives as Double Mutant Epidermal Growth Factor Receptor-L858R/T790M Tyrosine Kinase Inhibitors.

A series of 2,4-disubstituted pyrimidine derivatives bearing 5-substituted-1,3,4 thidiazole were devised and synthesized based on the binding mode of the approved drug Osimertinib with the ATP competitive site of EGFR-L858R/T790M in order to increase selectivity towards double mutant EGFR and potent antitumor activity. Their cellular bioactivity and corresponding enzyme inhibition were studied, and it was revealed that several compounds had significant biological activity and selectivity when compared to the control compounds. One of the most promising compound 8, substantially suppressed the proliferation of H1975 cells and showed significant inhibition of double mutant EGFR-L858R/T790M TK with IC values of 0.

Model organisms for investigating the functional involvement of NRF2 in non-communicable diseases.

Non-communicable chronic diseases (NCDs) are most commonly characterized by age-related loss of homeostasis and/or by cumulative exposures to environmental factors, which lead to low-grade sustained generation of reactive oxygen species (ROS), chronic inflammation and metabolic imbalance. Nuclear factor erythroid 2-like 2 (NRF2) is a basic leucine-zipper transcription factor that regulates the cellular redox homeostasis. NRF2 controls the expression of more than 250 human genes that share in their regulatory regions a cis-acting enhancer termed the antioxidant response element (ARE).

Discovery and biological evaluation of potent 2-trifluoromethyl acrylamide warhead-containing inhibitors of protein disulfide isomerase.

Protein disulfide isomerase (PDI) regulates multiple protein functions by catalyzing the oxidation, reduction, and isomerization of disulfide bonds. The enzyme is considered a potential target for treating thrombosis. We previously developed a potent PDI inhibitor, CPD, which contains the propiolamide as a warhead targeting cysteine residue in PDI.

Derivatives of D(-)-glutamine-based MMP-2 inhibitors as an effective remedy for the management of chronic myeloid leukemia-Part-III: Synthesis, biological screening and in silico binding interaction analysis.

Tyrosine kinase inhibitors (TKIs) have markedly improved the overall survival rate of patients with chronic myeloid leukemia (CML), enabling them to achieve a normal life expectancy. However, toxicity, relapse, and drug resistance continue to pose major challenges in the clinical treatment of CML. The progression of leukemia is directly connected to higher expression levels and enzymatic actions of matrix metalloproteinase-2 (MMP-2).

Phyto-pharmacological wonders of genus : Ethnopharmacological insights and phytochemical treasures from natural products.

Natural products have perennially served as a cornerstone for the genesis of novel medicinal compounds. Most clinical therapeutics originate from ancestral herbal remedies and their formulations. Scholars and practitioners have always aimed to extract better remedies to treat various ailments.

Leveraging artificial intelligence and machine learning to accelerate discovery of disease-modifying therapies in type 1 diabetes.

Progress in developing therapies for the maintenance of endogenous insulin secretion in, or the prevention of, type 1 diabetes has been hindered by limited animal models, the length and cost of clinical trials, difficulties in identifying individuals who will progress faster to a clinical diagnosis of type 1 diabetes, and heterogeneous clinical responses in intervention trials. Classic placebo-controlled intervention trials often include monotherapies, broad participant populations and extended follow-up periods focused on clinical endpoints. While this approach remains the 'gold standard' of clinical research, efforts are underway to implement new approaches harnessing the power of artificial intelligence and machine learning to accelerate drug discovery and efficacy testing.

Overcoming Challenges in Small-Molecule Drug Bioavailability: A Review of Key Factors and Approaches.

The bioavailability of small-molecule drugs remains a critical challenge in pharmaceutical development, significantly impacting therapeutic efficacy and commercial viability. This review synthesizes recent advances in understanding and overcoming bioavailability limitations, focusing on key physicochemical and biological factors influencing drug absorption and distribution. We examine cutting-edge strategies for enhancing bioavailability, including innovative formulation approaches, rational structural modifications, and the application of artificial intelligence in drug design.

Re-design and evaluation of diclofenac-based carborane-substituted prodrugs and their anti-cancer potential.

In this study, we investigated a novel anti-cancer drug design approach by revisiting diclofenac-based carborane-substituted prodrugs. The redesigned compounds combine the robust carborane scaffold with the oxindole framework, resulting in four carborane-derivatized oxindoles and a unique zwitterionic amidine featuring a nido-cluster. We tested the anti-cancer potential of these prodrugs against murine colon adenocarcinoma (MC38), human colorectal carcinoma (HCT116), and human colorectal adenocarcinoma (HT29).

Plasma p-tau217 in Alzheimer's disease: Lumipulse and ALZpath SIMOA head-to-head comparison.

Plasma phosphorylated-tau217 (p-tau217) has been shown to be one of the most accurate diagnostic markers for Alzheimer's disease. No studies have compared the clinical performance of p-tau217 as assessed by the fully automated Lumipulse and single molecule array (SIMOA) AlZpath p-tau217. The study included 392 participants, 162 with Alzheimer's disease, 70 with other neurodegenerative diseases with CSF biomarkers and 160 healthy controls.

Indian Shot ( L). Leaves Provide Valuable Insights into the Management of Inflammation and Other Associated Disorders Offering Health Benefits.

Background: Throughout history, plants have played a crucial role in advancing medicinal treatments by providing a diverse range of compounds for the development of innovative therapies. L. a tropical herb of the Cannaceae family, also known as Indian shot, has a rich history of traditional use in treating ailments like inflammation, malaria, dysentery, fever, dropsy, and diarrhea.

Unravelling the druggability and immunological roles of the SOCS-family proteins.

The Suppressor of Cytokine Signalling (SOCS) protein family play a critical role in cytokine signalling and regulation of the JAK/STAT pathway with functional consequences to the immune response. Members of this family are implicated in multiple different signalling cascades that drive autoimmune diseases and cancer, through their binding to phosphotyrosine modified proteins as well as ubiquitination activity as part of Cullin5 RING E3 ligases. Here we review the SOCS family members CISH and SOCS1-SOCS7, with a focus on their complex role in immunity.

π-HuB: the proteomic navigator of the human body.

The human body contains trillions of cells, classified into specific cell types, with diverse morphologies and functions. In addition, cells of the same type can assume different states within an individual's body during their lifetime. Understanding the complexities of the proteome in the context of a human organism and its many potential states is a necessary requirement to understanding human biology, but these complexities can neither be predicted from the genome, nor have they been systematically measurable with available technologies.

Neuroprotective Assessment of Nutraceutical (Betanin) in Neuroblastoma Cell Line SHSY-5Y: An in-Vitro and in-Silico Approach.

The cognitive dysfunction in the brain cause severe pathological consequences such as Alzheimer's disease (AD), Parkinson's disease. The current treatments are cost expensive and also cause negative side effects. Therefore it is inevitable to develop natural phyto-compounds as a drug like molecules to treat neurodegenerative diseases.

Identification of C-mannosylation in a receptor tyrosine kinase AXL.

C-mannosylation is a unique type of glycosylation in which a mannose is added to tryptophan in a protein. However, the biological function of C-mannosylation is still largely unknown. AXL is a receptor tyrosine kinase, and its overexpression contributes to tumor malignancy.

Ion channel modulator DPI-201-106 significantly enhances antitumor activity of DNA damage response inhibitors in glioblastoma.

Background: Glioblastoma, a lethal high-grade glioma, has not seen improvements in clinical outcomes in nearly 30 years. Ion channels are increasingly associated with tumorigenesis, and there are hundreds of brain-penetrant drugs that inhibit ion channels, representing an untapped therapeutic resource. The aim of this exploratory drug study was to screen an ion channel drug library against patient-derived glioblastoma cells to identify new treatments for brain cancer.

MIBiG 4.0: advancing biosynthetic gene cluster curation through global collaboration.

Specialized or secondary metabolites are small molecules of biological origin, often showing potent biological activities with applications in agriculture, engineering and medicine. Usually, the biosynthesis of these natural products is governed by sets of co-regulated and physically clustered genes known as biosynthetic gene clusters (BGCs). To share information about BGCs in a standardized and machine-readable way, the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard and repository was initiated in 2015.

Exploring the key structural attributes and chemico-biological interactions of pyridinone-based SARS-CoV-2 3CL inhibitors through validated structure-based drug design strategies.

The global outbreak of COVID-19 infection is the first pandemic the world has experienced in this 21 century. The novel coronavirus 2019 (nCoV-19) also called the SARS-CoV-2 is the reason behind the severe acute respiratory syndrome (SARS) that led to this worldwide crisis. In this current post-pandemic situation, despite having effective vaccines, the paucity of orally administrable drug molecules for such infections is a major drawback in this current scenario.

Inhibitors of malaria parasite cyclic nucleotide phosphodiesterases block asexual blood-stage development and mosquito transmission.

Cyclic nucleotide-dependent phosphodiesterases (PDEs) play essential roles in regulating the malaria parasite life cycle, suggesting that they may be promising antimalarial drug targets. PDE inhibitors are used safely to treat a range of noninfectious human disorders. Here, we report three subseries of fast-acting and potent PDEβ inhibitors that block asexual blood-stage parasite development and that are also active against human clinical isolates.

Identification of bioactive compounds with popular single-atom modifications: Comprehensive analysis and implications for compound design.

The extensive bioactivity data available in public databases, such as ChEMBL, has facilitated in-depth structure-activity relationship (SAR) analysis, which are essential for understanding the impact of molecular modifications on biological activity in a comprehensive manner. A central strategy in SAR analysis is the assessment of molecular similarity. Several approaches preferred by medicinal chemists have been developed to efficiently capture structurally related compounds on a large scale.