Potent EGFR/PARP-1 inhibition by spirooxindole-triazole hybrids for targeted liver cancer therapy.

The search for effective anti-cancer therapies has led to the exploration of dual inhibition strategies targeting multiple key molecular pathways. In this study, we aimed to design a novel candidate capable of dual inhibition targeting both EGFR (Epidermal Growth Factor Receptor) and PARP-1 (poly(ADP-ribose)polymerase-1), two crucial proteins implicated in cancer progression and resistance mechanisms. Through molecular hybridization and structure-based drug design approaches, we synthesized a series of compounds based on spirooxindole with triazole scaffolds with the potential for dual EGFR and PARP-1 inhibition.

Pharmacological investigation of selected 1,2,4 triazole derivative against ethanol induced gastric ulcer.

The present study aims to assess the therapeutic potential of (2S,3S,4S,5S,6S-2-(acetoxymethyl)-6-(4-chlorophenyl)-3-(pyridine-4-yl)5-thioxo-4,5-dihydro-1,2,4-triazol-1-yl tetrahydro-2H-pyran 3,4,5tryltriacetate (JAK05) on gastric ulcer. The current study was designed to evaluate the anti-ulcer potential of JAK05 against ethanol-induced gastric ulcer by employing in silico, in vitro and in vivo techniques. In silico studies, JAK05 has a binding score ranging from -8.

Assessment of binding affinity of major bioactive compounds from , , , , and to COX-2 receptor: an study.

In traditional medicine, potential anti-inflammatory and pain-relieving activity of and has been emphasized. In this study, we explored binding affinity of 36 bioactive compounds from these plants to cyclooxygenase-2 (COX-2) receptor using docking method. Six compounds namely, beta carotene, lycopene, lutein, momordicoside, rutin and azadirachtin showed excellent binding affinities (-10.

Unraveling Interleukin-1β inhibition: Computational insights into anti-inflammatory compound selection for inflammatory disorders.

The multifaceted impact of IL-1β has been proposed to have a central role in a spectrum of immunological responses spanning physiological reactions to aggressive inflammatory reactions and autoimmune disorders. Once IL-1β binds to its cognate receptor it initiates IL-1R1/TLR4 signaling cascade, leading to transcriptional modifications that sustain the inflammatory response. Extensive structural and functional investigations on IL-1β have yielded various inhibitors aimed at disrupting the formation of ligand receptor complex.

Exploring the diverse acetylcholinesterase inhibitory potential of girinimbine: insights from in vitro assays, molecular docking, and simulation studies.

The search for new treatments for Alzheimer's disease (AD) has led to the exploration of plant-based drugs as potential options. Acetylcholinesterase (AChE) inhibitors are widely used as anti-AD medications. This study aimed to investigate the inhibitory mechanism of girinimbine, a constituent of Murraya koenigii, on AChE.

Cinnamaldehyde ameliorates diabetes-induced biochemical impairments and AGEs macromolecules in a pre-clinical model of diabetic nephropathy.

Purpose: Cinnamaldehyde, has various therapeutic potentials including glucose-lowering effect, and insulinotropic effect; however, its glycation inhibitory mechanism is not known yet. In this study, we explored the effects of cinnamaldehyde for its AGEs inhibitory mechanism in a streptozotocin-complete Freund's adjuvant (STZ-CFA) induced diabetic nephropathy (DN) rat model.

Methods: Pre-clinical DN model was developed by the administration of multiple low doses of STZ-CFA in rats, mainly characterized by abnormal blood parameters and nephrotic damages.

Synthesis of arylated tetrahydrobenzo[]quinoline-3-carbonitrile derivatives as potential hits for treatment of diabetes.

Quinoline scaffolds are serving as the core structure for numerous antifungal, analgesic, antipyretic, anti-inflammatory drugs as well as have also been investigated for their potential antidiabetic properties. Though further exploration is required in this area as the current antidiabetic agents, such as acarbose, miglitol and voglibose, are associated with several adverse side effects. In this context, arylated tetrahydrobenzo[]quinoline-3-carbonitrile derivatives were designed and evaluated as potential antidiabetic agents.

Shifting paradigms: The promise of allosteric inhibitors against dengue virus protease.

Dengue, a mosquito-borne viral infection caused by the dengue virus (DENV), is a global health challenge. Annually, approximately 400 million cases are reported worldwide, signaling a persistent upward trend from previous years and projected a manifold increase in the future. There is a growing need for innovative and integrated approaches aimed at effective disease management.

Synthesis of isoniazid derivatives and evaluation of their α-chymotrypsin inhibitory effect through in silico guided in vitro studies.

Alpha-chymotrypsin is a serine protease. Its overexpression is responsible for several ailments, such as chronic obstructive pulmonary disease, autoimmune diseases, pancreatitis, and colon cancers. Therefore, the discovery of potent α-chymotrypsin inhibitors is essential for the treatment of the aforementioned ailments.

Novel spirooxindole-triazole derivatives: unveiling [3+2] cycloaddition reactivity through molecular electron density theory and investigating their potential cytotoxicity against HepG2 and MDA-MB-231 cell lines.

A novel analogue of hybrid spirooxindoles was synthesized employing a systematic multistep synthetic approach. The synthetic protocol was designed to obtain a series of spirooxindole derivatives incorporating triazolyl--triazine framework via [3 + 2] cycloaddition (32CA) reaction of azomethine ylide ( with the corresponding chalcones . Unexpectedly, the reaction underwent an alternate route, leading to the cleavage of the s-triazine moiety and yielding a series of spirooxindole derivatives incorporating a triazole motif.

Molecular pathology and computational profiling of Janus kinase 2 (JAK2) mutation in acute lymphoblastic leukemia: insights from a Pakistani cohort.

Background: JAK2 mutation plays a clinically significant role in the pathogenesis of acute lymphoblastic leukemia (ALL) by enhancing its oncogenicity. The study aimed to characterize the molecular pathology and computational profile of the JAK2 mutation in an ALL cohort of Pakistani origin.

Methods: Ninety-three patients were enrolled in the current study.

Targeting glucosyltransferases to combat dental caries: Current perspectives and future prospects.

The emergence of antimicrobial resistance within bacterial communities poses formidable challenges to existing therapeutic strategies aimed at mitigating biofilm-mediated infections. Recent advancements in this domain have spurred the development of targeted antimicrobial agents, designed to selectively eradicate the primary etiological agents while preserving the beneficial microbial diversity of the oral cavity. Targeting glucosyltransferases (GTFs), which play crucial roles in dental biofilm formation, offers a precise strategy to inhibit extracellular polysaccharide synthesis without compromising oral microbiota.

Mechanistic insight into the mode of inhibition of dietary flavonoids; targeting macrophage migration inhibitory factor.

The Macrophage Migration Inhibitory Factor (MIF), a key pro-inflammatory mediator, is responsible for modulating immune responses. An array of inflammatory and autoimmune diseases has been linked to the dysregulated activity of MIF. The significance in physiological as well as pathophysiological phenomena underscores the potential of MIF as an attractive target with pharmacological relevance.

Impact of mutations in SARS-CoV-2 recombinant sub-variant XBB.1.16 on the binding affinity with human ACE2 receptor.

Despite the waning threat of the COVID-19 pandemic, its detrimental impact on global health persists. Regardless of natural immunity or immunity obtained through vaccination, emerging variants of the virus continue to undergo mutations and propagate globally. The persistent mutations in SARS-CoV-2, along with the subsequent formation of recombinant sub-variants has become a challenge for researchers and health professionals, raising concerns about the efficacy of current vaccines.

Imidazole-thiadiazole hybrids: A multitarget de novo drug design approach, in vitro evaluation, ADME/T, and in silico studies.

A library of imidazole-thiadiazole compounds (1-24) was synthesized to explore their therapeutic applications. The compounds were subjected to meticulous in vitro evaluation against α-glucosidase, α-amylase, acetylcholinesterase (AChE), and butylcholinesterase (BChE) enzymes. Compounds were also investigated for antioxidant activities using cupric reducing antioxidant capacity (CUPRAC), ferric reducing antioxidant power (FRAP), and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assays.

Exploring the mechanism of action of spirooxindoles as a class of CDK2 inhibitors: a structure-based computational approach.

Cyclin-dependent kinase 2 (CDK2) regulates cell cycle checkpoints in the synthesis and mitosis phases and plays a pivotal role in cancerous cell proliferation. The activation of CDK2, influenced by various protein signaling pathways, initiates the phosphorylation process. Due to its crucial role in carcinogenesis, CDK2 is a druggable hotspot target to suppress cancer cell proliferation.

Predicting FFAR4 agonists using structure-based machine learning approach based on molecular fingerprints.

Free Fatty Acid Receptor 4 (FFAR4), a G-protein-coupled receptor, is responsible for triggering intracellular signaling pathways that regulate various physiological processes. FFAR4 agonists are associated with enhancing insulin release and mitigating the atherogenic, obesogenic, pro-carcinogenic, and pro-diabetogenic effects, normally associated with the free fatty acids bound to FFAR4. In this research, molecular structure-based machine-learning techniques were employed to evaluate compounds as potential agonists for FFAR4.

Rhodanine-benzamides as potential hits for α-amylase enzyme inhibitors and radical (DPPH and ABTS) scavengers.

A series of 3-substituted and 3,5-disubstituted rhodanine-based derivatives were synthesized from 3-aminorhodanine and examined for α-amylase inhibitory, DPPH (1,1-diphenyl-2-picrylhydrazyl) and ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging activities in vitro. These derivatives displayed significant α-amylase inhibitory potential with IC values of 11.01-56.

Evaluation of chalcones as new glycogen phosphorylase inhibitors - an and approach.

Diabetes mellitus (DM) remains one of the pivotal diseases that have drawn the attention of researchers recently and during the last few decades. Due to its devastating symptoms, attempts to develop new drugs with mild side effects have resulted in a number of drugs that are functioning through various mechanisms. Among these, Glycogen phosphorylase (GP) inhibitors emerged as a new strategy for combating DM.

Uncovering PPAR-γ agonists: An integrated computational approach driven by machine learning.

Peroxisome proliferator-activated receptor gamma (PPAR-γ) serves as a nuclear receptor with a pivotal function in governing diverse facets of metabolic processes. In diabetes, the prime physiological role of PPAR-γ is to enhance insulin sensitivity and regulate glucose metabolism. Although PPAR-γ agonists such as Thiazolidinediones are effective in addressing diabetes complications, it is vital to be mindful that they are associated with substantial side effects that could potentially give rise to health challenges.

Taming the cytokine storm: small molecule inhibitors targeting IL-6/IL-6α receptor.

Given the increasing effectiveness of immune-based therapies, management of their associated toxicities is of utmost importance. Cytokine release syndrome (CRS), characterized by elevated levels of cytokine, poses a significant challenge following the administration of antibodies and CAR-T cell therapies. CRS also contributes to multiple organ dysfunction in severe viral infections, notably in COVID-19.

A deep learning-based theoretical protocol to identify potentially isoform-selective PI3Kα inhibitors.

Phosphoinositide 3-kinase alpha (PI3Kα) is one of the most frequently dysregulated kinases known for their pivotal role in many oncogenic diseases. While the side effects linked to existing drugs against PI3Kα-induced cancers provide an avenue for further research, the significant structural conservation among PI3Ks makes it extremely difficult to develop new isoform-selective PI3Kα inhibitors. Embracing this challenge, we herein designed a hybrid protocol by integrating machine learning (ML) with in silico drug-designing strategies.