Exploring the potential of EphA2 receptor signaling pathway: a comprehensive review in cancer treatment.

The protein encoded by the ephrin type-A receptor 2 (EphA2) gene is a member of the ephrin receptor subfamily of the receptor tyrosine kinase family (RTKs). Eph receptors play a significant role in various biological processes, particularly cancer progression, development, and pathogenesis. They have been observed to regulate cancer cell growth, migration, invasion, tumor development, invasiveness, angiogenesis, and metastasis. To target EphA2 activity, various molecular, genetic, biochemical, and pharmacological strategies have been extensively tested in laboratory cultures and animal models. Notably, drugs, such as dasatinib, initially designed to target the kinase family, have demonstrated an additional capability to target EphA2 activity. Additionally, a novel monoclonal antibody named EA5 has emerged as a promising option to counteract the effects of EphA2 overexpression and restore tamoxifen sensitivity in EphA2-transfected MCF-7 cells during in vitro experiments. This antibody mimicked the binding of Ephrin A to EphA2. These methods offer potential avenues for inhibiting EphA2 activity, which could significantly decelerate breast cancer progression and restore sensitivity to certain drugs. This review article comprehensively covers EphA2's involvement in multiple malignancies, including ovarian, colorectal, breast, lung, glioma, and melanoma. Furthermore, we discuss the structure of EphA2, the Eph-Ephrin signaling pathway, various EphA2 inhibitors, and the mechanisms of EphA2 degradation. This article provides an extensive overview of EphA2's vital role in different types of cancers and outlines potential therapeutic approaches to target EphA2, shedding light on the underlying molecular mechanisms that make it an attractive target for cancer treatment.

Identifying potential inhibitors of C-X-C motif chemokine ligand10 against vitiligo: structure-based virtual screening, molecular dynamics simulation, and principal component analysis.

The research aims to envisage small molecule inhibitors targeting the C-X-C motif chemokine ligand 10 (CXCL10) of the JAK/STAT pathway. CXCL10 plays a significant role in inducing auto-immunity in vitiligo through JAK/STAT pathway. To accomplish the aim, structure-based virtual screening with fundamental search limits, e.g., molecular weight (MW ≤ 500 Da), hydrogen bond donor (HBD ≤ 5), hydrogen bond acceptor (HBA ≤ 10), and lipophilicity (logP ≤ 5) was used to screen investigational molecules from MCULE database. The SBVS-ligand hits were sifted through toxicity profiling followed by filtration through the Brain or IntestinaL EstimateD-Egg model to check the human intestinal abortion and blood-brain barrier permeation based on two physicochemical properties, including topological surface area and WLOGP. The BOILED-Egg filtered compounds were passed through drug-likeness features other than Pfizer's Lipinski rule of five, viz., Ghose filters, Muegge filters, Egan parameters, and Veber filters, followed by medicinal chemistry's pan assay interference structure and Brenk alert investigation. Chemical compounds that comply with the above ADME descriptors were docked with target protein CXCL10 via AutoDock Vina. The stability of the top two ligand hits was assessed through dynamics simulations of 100 ns and principal component analysis and compared with the reference drugs Baicalein and EGCG. Based on the findings of Gibbs free energy of binding, ADME profiling, medicinal chemistry attributes depiction, root-mean-square deviation, root-mean-square fluctuation, solvent accessible surface area, the free energy of solvation, the radius of gyration, and PCA, MCULE2726078782-0-2 was found better than potential reference drug Baicalein.Communicated by Ramaswamy H. Sarma.

CXCL10 plays a significant role in inducing auto-immunity in vitiligo through JAK/STAT pathway.The present study identifies the small molecule as a potential inhibitor of CXCL10 using SBVS, MD simulation, and PCA.Ten ligand hits have been identified as having better binding propensity than the known inhibitor Baicalein.MCULE2726078782-0-2 may be suggested as a therapeutic agent to inhibit CXCL10 because it has all the druggable properties necessary to specify an oral drug molecule.

Identifying the alpha-glucosidase inhibitory potential of dietary phytochemicals against diabetes mellitus type 2 via molecular interactions and dynamics simulation.

The research aims to identify the inhibitory potential of natural dietary phytochemicals against non-insulinotropic target protein alpha-glucosidase and its possible implications to diabetes mellitus type 2. A data set of sixteen plant-derived dietary molecules viz., 4,5-dimethyl-3-hydroxy-2(5H)-furanone, apigenin, bromelain, caffeic acid, cholecalciferol, dihydrokaempferol 7-o-glucopyranoside, galactomannan, genkwanin, isoimperatorin, luteolin, luteolin 7-o-glucoside, neohesperidin, oleanoic acid, pelargonidin-3-rutinoside, quercetin, and quinic acid were taken to accomplish molecular docking succeeded by their comparison with known inhibitors including acarbose, miglitol, voglibose, emiglitate, and 1-deoxynojirimycin. Among all phyto-compounds, bromelain (ΔG: -9.54 kcal/mol), cholecalciferol (-8.47 kcal/mol), luteolin (-9.02 kcal/mol), and neohesperidin (-8.53 kcal/mol) demonstrated better binding interactions with alpha-glucosidase in comparison to the best-known inhibitor, acarbose (ΔG: -7.93 kcal/mol). Molecular dynamics simulation of 10 ns duration, CYP450 site of metabolism identification, and prediction of activity spectra for substances depicted the bromelain as the most stable inhibitor compared to luteolin and acarbose. Findings of molecular interactions, molecular dynamics study, metabolism, and biological activity prediction proved bromelain as a potential alpha-glucosidase inhibitor. Thus, bromelain might be helpful as an insulin-independent therapeutic molecule towards controlling and managing diabetes mellitus type 2.

Target-based virtual screening, computational multiscoring docking and molecular dynamics simulation of small molecules as promising drug candidate affecting kinesin-like protein KIFC1.

The kinesin family member C1 (KIFC1) is an essential protein that facilitates the bipolar division of neoplastic cells. Inhibiting KIFC1 by small molecules is a lucrative strategy to impede bipolar mitosis leading to the apoptosis of cancerous cells. The research aims to envisage small-molecule inhibitors targeting KIFC1. The Mcule database, a comprehensive online digital platform containing more than five million chemical compounds, was used for structure-based virtual screening (SBVS). Druglikeness filtration sifted 2,293,282 chemical hits that further narrowed down to 49 molecules after toxicity profiling. Finally, 39 compounds that comply with the BOILED-Egg permeation predictive model of the ADME rules were carried forward for multiscoring docking using the AutoDock Vina inbuilt to Mcule drug discovery platform, DockThor and SwissDock tools. The mean of ΔG terms produced by docking tools was computed to find consensus top ligand hits. AZ82 exhibited stronger binding (Consensus ΔG: -7.99 kcal mol-1 ) with KIFC1 among reference inhibitors, for example, CW069 (-7.57 kcal mol-1 ) and SR31527 (-7.01 kcal mol-1 ). Ten ligand hits namely, Mcule-4895338547 (Consensus ΔG: -8.69 kcal mol-1 ), Mcule-7035674888 (-8.42 kcal mol-1 ), Mcule-5531166845 (-8.53 kcal mol-1 ), Mcule-3248415882 (-8.55 kcal mol-1 ), Mcule-291881733 (-8.41 kcal mol-1 ), Mcule-5918624394 (-8.44), Mcule-3470115427 (-8.47), Mcule-3686193135 (-8.18 kcal mol-1 ), Mcule-3955355291 (8.09 kcal mol-1 ) and Mcule-9534899193 (-8.01 kcal mol-1 ) depicted strong binding interactions with KIFC1 in comparison to potential reference inhibitor AZ82. The top four ligands and AZ82 were considered for molecular dynamics simulation of 50 ns duration. Toxicity profiling, physicochemical properties, lipophilicity, solubility, pharmacokinetics, druglikeness, medicinal chemistry attributes, average potential energy, RMSD, RMSF, SASA, ΔGsolv and Rg analyses forecast the ligand mcule-4895338547 as a promising inhibitor of KIFC1.