Vivek Asati

Alzheimer’s disease (AD) is a chronic, progressive neurodegenerative disorder predominantly affecting 47 million people worldwide. Dysregulation of BACE-1, the initiating enzyme in the amyloidogenic cascade, plays a pivotal role in AD pathogenesis. Conventional anticholinesterase inhibitors can only provide symptomatic relief without stopping disease progression. In this study, we employed an integrated computational approach to rationally design novel indole-based BACE-1 inhibitors through pharmacophore modeling, 3D-QSAR analysis, ligand–protein docking, pharmacophore-guided virtual screening, MD simulation, and ADME studies. DDHRR_1 was identified as the best pharmacophore model with a survival score of 5.7767. Statistically significant 3D-QSAR models were obtained, wherein the atom-based model demonstrated high predictive reliability ([Formula: see text]), while the field-based model exhibited acceptable predictive ability ([Formula: see text]). Among the dataset compounds, compound B38 (3i) displayed the optimal binding affinity (−6.567 kcal/mol; PDB ID: 4DJU), with key interactions at GLY95, TYR132, and PHE169. [Formula: see text]-group enumeration generated 2408 derivatives, among which [Formula: see text]1 and [Formula: see text]2 exhibited strong binding affinity (−10.339 kcal/mol and −9.611 kcal/mol). A comparative analysis of the referenced ligand, the two best-performing ZINC-derived compounds (ZINC43707325 and ZINC03628223), and the two top-ranked [Formula: see text]-group compounds revealed that [Formula: see text]2 was the major lead compound. However, as these findings are based solely on in-silico analyses, further synthesis, biological evaluation, and BBB permeability studies are necessary to validate the therapeutic potential of [Formula: see text]2 against Alzheimer’s disease.

Pim‐1, a carcinogenic threonine and serine kinase, inhibits apoptosis and advances the cell cycle. It is overexpressed in several human cancers. The proviral integration site of Moloney murine leukemia virus 1 is Pim‐1. Previous studies have shown that the Pim‐1 30‐UTR regulates the stability of Pim‐1 mRNA. Threonine and serine are identified as the proto‐oncogene Pim‐1 kinase. Pim‐1 mediates numerous biological processes, including apoptosis, cell division, proliferation, and cancer. Pim‐1‐mediated anticancer activity has been reported in several analogs of thiazole/ bis ‐thiazole, tetrazine, thiophenes, quinoline, pyrazolopyrimidine, 3‐cyanopyridine, thiazolidine‐2,4‐dione, thieno[2,3‐ b ]pyridine, triazolo[4,3‐ b ]pyridazine, pyrazolo[1,5‐ a ]pyrimidines, and pyrazolo[3,4‐ b ]pyridine derivatives. Additionally, flavonoids and amino alcohol compounds that constitute Pim‐1‐mediated cancer therapy have also been identified thus far. Many compounds with Pim‐1‐mediated cytotoxicity have been discovered up to this point, and scientists are currently concentrating on bringing novel compounds with anticancer potential to the market.

1. Diabetes mellitus (DM) is a long-term, chronic condition that has been worsening health of people all around the globe in the recent years [1]. Sedentary lifestyle including lack of exercise, ba...

As the first member of the receptor tyrosine kinase family, epidermal growth factor (EGFR) has been linked to human cancers through numerous lines of evidence. Research on EGFR has also led to the development of several key theories regarding cancer progression. Through a vast array of paracrine loops, each of which regulates a crucial stage in the metastasis cascade, EGFR not only maintains cell proliferation but also confers resistance to anti‐cancer cytotoxic treatments. To identify EGFR tyrosine kinase inhibitors (TKIs), simulation studies have been used to produce several small molecules, especially those containing quinazolines. The design process also evaluated the emergence of resistance problems and epigenetic changes, which eventually reduced drug efficacy and made it clear that more study in this field was required. The genetic changes taking place in the EGFR tyrosine kinase domain have been thoroughly studied in recent decades. These changes have made it possible to create highly effective inhibitors. The structure–activity relationship (SAR) and cytotoxic activity of several quinazoline derivatives with demonstrated EGFR‐inhibitory antiproliferative activity are highlighted in this review. In the present paper, we report the EGFR‐mediated anticancer potential of quinazoline derivatives discovered after 2020.

PROTACs, also called proximity-inducing agents, are chimeric molecules composed of a ligand for protein of interest (POI), an E3 ligase ligand and a linker connecting them. PROTACs have transformed the therapeutic landscape by enabling an event-driven strategy to degrade disease-associated proteins previously regarded as undruggable. The unique event-driven mechanism of PROTACs allows selective protein degradation with greater potency and lower drug resistance than conventional occupancy-based inhibitors. Despite their advantages, challenges such as high molecular weight, low permeability, poor pharmacokinetic properties restrict their clinical applications. To overcome these limitations, AI-driven technologies are being utilised to generate novel, chemically valid PROTACs. This review highlights the drawbacks of conventional computational methods and explores emerging AI-driven tools applied to multiple areas of PROTAC research, such as target (POI) selection (DeepUSI, DrugnomeAI), linker generation (AIMLinker, DiffLinker), activity prediction (AI-DPAPT, DeepPROTAC), POI degradability assessment (PrePROTAC, MAPD), ternary complex modelling (ProFlow), PROTAC generation (PROTAC-RL), and ADME property estimation (MT-GNN). It also outlines current challenges such as data scarcity, reproducibility issues, inadequate model generalizability, emphasizing the need for hybrid models or integrated AI techniques to mitigate these limitations.

The study aims to design, synthesize, and evaluate novel furan-clubbed 1,2,3-triazole derivatives as potential α-glucosidase inhibitors for the management of diabetes mellitus. Ten furan-clubbed-1,2,3-triazole derivatives PD(1-10) were synthesized and characterized through sophisticated instrumentation techniques, including FT-IR, ¹H NMR, ¹³C NMR, and LC-MS. The compounds were assessed in vitro for their ability to inhibit the α-glucosidase enzyme. The in vivo antidiabetic effect of the best molecules was evaluated using STZ-nicotinamide induced diabetic mouse model. The observed results were further supported by molecular docking against α-glucosidase (PDB ID: 3L4U) and histopathological examinations. The results of in vitro studies showed that the test compound PD-10 exhibited the strongest α-glucosidase inhibition (IC₅₀ = 13.82 μM), outperforming acarbose (IC₅₀ = 32.03 μM), followed by PD-1 and PD-6. Further, the in vivo antidiabetic evaluation of the best compounds adjudged compound PD-10 as the best molecule among the series. Docking analyses indicated a significant binding affinity of PD-10 (-4.34 kcal/mol). The research highlights PD-10 as a promising α-glucosidase inhibitor with strong in vitro and in vivo antidiabetic effects, supported by favorable molecular docking interactions, and emphasizes its potential for development as an antidiabetic lead for further studies and evaluations.

To design, synthesize, and evaluate novel pyrimidine-triazole derivatives as epidermal growth factor receptor (EGFR) inhibitors for anticancer activity. Ten derivatives (SM-1A to SM-1J) were synthesized and assessed for cytotoxicity against A549 lung cancer cell line also performed EGFR inhibition assay. Molecular docking was performed on the ATP binding pocket of EGFR (PDB: 1XKK). Compounds SM-1F and SM-1 G exhibited good cytotoxic activity (IC₅₀ = 0.5 and 0.7 µM) than standard drug erlotinib (IC₅₀ = of 0.9 µM). Compound SM-1F showed a good binding score -8.93 kcal/mol and interactions with amino acid residues THR 854, THR 790, CYS 775, and PHE856. The results showed SM-1F may be used as a lead compound for further development of novel EGFR inhibitors.

Aberrant expression of bruton’s tyrosine kinase (BTK) plays a major role in progression of B-cell malignancies and autoimmune disorders, highlighting the need for effective and selective BTK inhibitors. A series of 45 pyrrolopyrimidine derivatives were selected for in-silico study from the literature. A 3D-QSAR and pharmacophore model was utilized to design novel compounds; they were subsequently generated through R group enumeration based on the QSAR data and further evaluated through molecular docking and virtual screening. The model AADHR_1 was chosen as the best pharmacophore model. The 3D-QSAR analysis yielded statistically robust models. The atom based model exhibited excellent correlation coefficient (R² = 0.8831), and cross validation coefficient (Q² = 0.8675), while the field based demonstrated correlation coefficient of R²=0.8498 and Q²=0.855. A total for 1752 compounds were generated through R group enumeration for production of new compounds. Among them R1 demonstrated the best binding affinity (- 7.87 kcal/mol, PDB ID: 5P9J) with key binding interactions at TYR551, GLN412, and LYS430. Molecular dynamics (MD) simulations further confirmed the stability of these interactions under dynamics conditions. Furthermore, ADME and physiochemical properties confirmed drug likeness, bioavailability, and a favourable pharmacokinetic profile of the designed compounds. Among the designed compounds, R1 exhibited the highest binding affinity, superior interaction stability in MD simulations, and balanced ADME characteristics, making it most potent. Overall, this study provides considerable insights into the rational computational design of pyrrolopyrimidine based BTK inhibitors for advancing these candidates into experimental validation and clinical advancement.