Owing to several mutations, the oncogene Kirsten rat sarcoma 2 viral homolog (KRAS) is activated in majority of cancers, and targeting it has been pharmacologically challenging. In this study, using an silico approach comprised pharmacophore modeling, molecular docking, dynamics simulations, potential KRAS G12D inhibitors were investigated. A ligand-based common feature model was generated identify framework necessary for effective inhibition. The chemical features selected two hydrogen bond...

Proteasome inhibitors (PIs) constitute the first line of therapy for multiple myeloma (MM). Despite impressive clinical efficacy, MM remains fatal due to development drug resistance over time. During progression, stress responses hypoxia and PIs suppress mammalian target rapamycin complex 1 (mTORC1) activity by releasing tuberous sclerosis 2 (TSC2), which deactivates Ras homologue enriched in brain (Rheb), a crucial regulator mTORC1. The efficacy targeting is enhanced when mTORC1...

Breast cancer is one of the major impediments affecting women globally. The ATP-dependant heat shock protein 90 (Hsp90) forms central component molecular chaperone machinery that predominantly governs folding newly synthesized peptides and their conformational maturation. It regulates stability function numerous client proteins are frequently upregulated and/or mutated in cells, therefore, making Hsp90 inhibition a promising therapeutic strategy for development new efficacious drugs to treat...

Progeria is a globally noticed rare genetic disorder manifested by premature aging with no effective treatment. Under these circumstances, farnesyltransferase inhibitors (FTIs) are marked as promising drug candidates. Correspondingly, pharmacophore model was generated exploiting the features of lonafarnib. The selected allowed to screen InterBioScreen natural compound database retrieve potential lead A series filtering steps were applied assess drug-likeness compounds. obtained compounds...

The rapid spread of COVID-19, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a worldwide health emergency. Unfortunately, to date, very small number remedies have been be found effective against SARS-CoV-2 infection. Therefore, further research required achieve lasting solution this deadly disease. Repurposing available drugs and evaluating natural product inhibitors target proteins could an approach accelerate drug discovery development. With strategy...

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase portraying quintessential role in cellular proliferation and survival. Aberrations the mTOR signaling pathway have been reported numerous cancers including thyroid, lung, gastric ovarian cancer, thus making it therapeutic target. To attain this objective, an silico investigation was designed, employing pharmacophore modeling approach. A structure-based (SBP) model exploiting key features selective inhibitor, Torkinib...

The cyclin-dependent kinase 7 (CDK7) plays a crucial role in regulating the cell cycle and RNA polymerase-based transcription. Overexpression of this is linked with various cancers humans due to its dual involvement development. Furthermore, emerging evidence has revealed that inhibiting CDK7 anti-cancer effects, driving development novel more cost-effective inhibitors enhanced selectivity for over other CDKs. In present investigation, pharmacophore-based approach was utilized identify...

Spleen tyrosine kinase (SYK) is an essential mediator of immune cell signaling and has been anticipated as a therapeutic target for autoimmune diseases, notably rheumatoid arthritis, allergic rhinitis, asthma, cancers. Significant attempts have undertaken in recent years to develop SYK inhibitors; however, limited success achieved due poor pharmacokinetics adverse effects inhibitors. The primary goal this research was identify potential inhibitors having high affinity, selectivity based on...

Drug resistance is a core issue in cancer chemotherapy. A known folate antagonist, methotrexate (MTX) inhibits human dihydrofolate reductase (hDHFR), the enzyme responsible for catalysis of 7,8-dihydrofolate reduction to 5,6,7,8-tetrahydrofolate, biosynthesis and cell proliferation. Structural change DHFR significant cause subsequent loss MTX. In current study, wild type hDHFR double mutant (engineered variant) F31R/Q35E (PDB ID: 3EIG) were subject computational study. Structure-based...

Identification of natural product inhibitors against rearranged during transfection (RET) tyrosine kinase as cancer therapeutics using combination in silico techniques.

Breast cancer (BC) is the leading cause of death among women worldwide devoid effective treatment. It therefore important to develop agents that can reverse, reduce, or slow growth BC. The use natural products as chemopreventive provides enormous advantages. aim current investigation determine efficacy phytochemicals against BC along with approved drugs screen most desirable and phytocompound. In study, 36 have been evaluated aromatase identify potential candidate drug employing Cdocker...

The concept of hybrid drugs for targeting multiple aberrant pathways cancer, by combining the key pharmacophores clinically approved single-targeted drugs, has emerged as a promising approach overcoming drug-resistance. Here, we report design unique molecules two BCR-ABL inhibitor (ponatinib) and HDAC (vorinostat) results in vitro studies drug-resistant CML cells. Robust 2D-QSAR 3D-pharmacophore machine learning supervised models were developed virtual screening based on their predicted...

Background: Activated Cdc42-associated kinase (ACK1) is essential for numerous cellular functions, such as growth, proliferation, and migration. ACK1 signaling occurs through multiple receptor tyrosine kinases; therefore, its inhibition can provide effective antiproliferative effects against human cancers. A number of ACK1-specific inhibitors were designed discovered in the previous decade, but none have reached clinic. Potent selective are urgently needed. Methods: In present investigation,...

Angiogenesis is defined as the formation of new blood vessels and a key phenomenon manifested in host cancers during which tyrosine kinases play crucial role. Vascular endothelial growth factor receptor-2 (VEGFR-2) pivotal cancer angiogenesis, warrants urgency discovering anti-angiogenic inhibitors that target signalling pathways. To obtain this objective, structure-based pharmacophore model was built from drug VEGFR-2 (PDB code: 4AG8), complexed with axitinib subsequently validated employed...

The novel coronavirus (SARS-CoV-2) outbreak has started taking away the millions of lives worldwide. Identification known and approved drugs against disease (COVID-19) seems to be an urgent need for repurposing existing drugs. So, here we examined a safe strategy using SuperDRUG2 database modeled membrane protein (M-protein) SARS-CoV-2 which is essential virus assembly by molecular docking-based virtual screening. A total 3639 from additionally 14 potential reported COVID-19 proteins were...

Protein-protein interactions are indispensable physiological processes regulating several biological functions. Despite the availability of structural information on protein-protein complexes, deciphering their complex topology remains an outstanding challenge. Raf kinase inhibitory protein (RKIP) has gained substantial attention as a favorable molecular target for numerous pathologies including cancer and Alzheimer’s disease. RKIP interferes with RAF/MEK/ERK signaling cascade by...

Heparanase (Hpse) is an endo-β-D-glucuronidase capable of cleaving heparan sulfate side chains. Its upregulated expression implicated in tumor growth, metastasis and angiogenesis, thus making it attractive target cancer therapeutics. Currently, a few small molecule inhibitors have been reported to inhibit Hpse, with promising oral administration pharmacokinetic (PK) properties. In the present study, ligand-based pharmacophore model was generated from dataset well-known active Hpse which were...

: Mechanistically, neurotoxic insults provoke Ca2+-mediated calpain activation, which cleaves the cytoplasmic region of membrane-embedded p35 and produces its truncated form p25. Upon physical interaction, cyclin-dependent kinase 5 (Cdk5) p25 forms hyperactivated Cdk5/p25 complex causes severe neuropathological aberrations including hyperphosphorylated tau-mediated neurofibrillary tangles formation, Alzheimer's symptoms, neuronal death. Therefore, inhibition may relieve p-tau-mediated...

Non-small cell lung cancer (NSCLC) is a lethal non-immunogenic malignancy and proto-oncogene ROS-1 tyrosine kinase one of its clinically relevant oncogenic markers. The inhibitor, crizotinib, demonstrated resistance due to the Gly2032Arg mutation. To curtail this resistance, researchers developed lorlatinib against mutated kinase. In present study, receptor-ligand pharmacophore model exploiting key features binding with was exploited identify inhibitors wild-type (WT) mutant (MT) domain....

Widely used in global households, fenugreek is well known for its culinary and medicinal uses. The various reported properties of are by virtue the different natural phytochemicals present it. Regarded as a promising target, interleukin 2 receptor subunit alpha (IL2Rα) has been shown to influence immune responses. In research, using silico techniques, we have demonstrated potential IL2Rα binding three polyphenol stilbenes (desoxyrhaponticin, rhaponticin, rhapontigenin) from fenugreek. As...

Raf kinase inhibitory protein (RKIP) is an essential regulator of the Ras/Raf-1/MEK/ERK signaling cascade and functions by directly interacting with Raf-1 kinase. The abnormal expression RKIP linked numerous diseases including cancers, Alzheimer's diabetic nephropathy. Interestingly, also plays indispensable role as a tumor suppressor, thus making it attractive therapeutic target. To date, only few small molecules have been reported to modulate activity RKIP, there need explore additional...