Insilco and Invitro approaches identify novel dual PI3K/AKT pathway inhibitors to control acute myeloid leukemia cell proliferations

Abohassan, Mohammad; Al-Shahrani, Mesfer; Alshahrani, Mohammad Y.; Rajagopalan, Prasanna

doi:10.1007/s12032-022-01846-1

Cited by 15 publications

(18 citation statements)

References 23 publications

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Section: Methodsmentioning

confidence: 99%

“…Diversity‐based high‐throughput docking technology developed by SiBioLead LLP (https://sibiolead.com/) 13 was used for screening the whole ZINC natural products library. Autodock‐vina for docking calculations was used as a docking algorithm for screening compounds 13 . For ranking target ligands, first, the diverse sets of molecules (scaffolds) from the ZINC natural product library, ∼175,000 molecules, were docked against the target protein.…”

Section: Methodsmentioning

confidence: 99%

“…For ranking target ligands, first, the diverse sets of molecules (scaffolds) from the ZINC natural product library, ∼175,000 molecules, were docked against the target protein. Based on the predicted docking energies, top 10 scaffolds or diverse molecules were selected and all the structurally related molecules, based on tanimoto scores, for each of the top 10 scaffolds were retrieved from the pre‐build ZINC natural product library and docked again (stage II docking) to the target protein 13 . All docking calculations were performed in high‐throughput mode, that is, vina exhaustiveness of 1.…”

Section: Methodsmentioning

confidence: 99%

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Computational modeling and in vitro evaluation identified natural product—Z218 as a novel Janus kinase 2 (JAK2) inhibitor to combat β‐thalassemia

Shaikh

2023

Biotech and App Biochem

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Aberrant activity of Janus kinase 2 (JAK2) is a known driver of several myeloproliferative disorders, including polycythemia vera, and thalassemia. Several inhibitors have been proposed to inhibit JAK2 activity in order to control the disease progression. Ruxolitinib and fedratinib that targets JAK2 kinase have been approved for use in myeloproliferative neoplasms patients. Experimental structures of JAK2 complexed with ruxolitinib provide insights into critical interactions of ruxolitinib. In this work, using a high‐throughput virtual screening followed by experimental validations, we have identified a novel natural product from ZINC database that interacts with JAK2 in a manner similar to ruxolitinib and inhibits the activity of JAK2 kinase. Molecular dynamics simulations and MMPBSA method show binding dynamics and stability of our identified lead compound. Kinase inhibition assays show that our identified lead molecule inhibits JAK2 kinase at a nanomolar range, indicating a plausibility that the identified lead molecule can be further studied as natural product inhibitor of JAK2 kinase.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Computational modeling and in vitro evaluation identified natural product—Z218 as a novel Janus kinase 2 (JAK2) inhibitor to combat β‐thalassemia

Shaikh

2023

Biotech and App Biochem

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“…These proteins can either be upregulated, silenced, or otherwise manipulated to restore or maintain proteostatic equilibrium [Figure 2]. Drugs can be screened and evaluated for affinity to these proteins by methods employed previously [157][158][159][160][161][162] , thus regulating their activity or interactions. Mitochondrial and ER proteins (e.g., PERK, IRE1, eiF2α, BiP, CHOP, GRP78, XBP1, ATF6, and ATF4) are known to be altered in diverse neurodegenerative diseases, and may be similarly aberrant in cardiac tissue, leading to protein aggregation and cardiomyopathy.…”

Section: Therapeutic Implications Of Impaired Protein Homeostasismentioning

confidence: 99%

“…Since dysfunctions of proteasomes and autophagy have been implicated in aging and age-related diseases, with consequences as diverse as those of Alzheimer's disease and CVD, small molecules targeting influential aggregate proteins may also benefit those afflicted with a wide range of other age-associated conditions [167,168] . Targeting these aggregate-specific proteins with small molecules rescued aggregateassociated functional declines in AD models [155,157,160,166,169] . In view of the substantial overlaps between proteins sequestered into aggregates in aged, hypertensive and post-MI hearts, these aggregate-specific proteins and their interfaces (especially the shared protein sets) offer attractive drug targets to relieve protein aggregation and its associated physiological impairments.…”

Section: Therapeutic Implications Of Impaired Protein Homeostasismentioning

confidence: 99%

ASGR1 and cholesterol: connecting the dots

Hólm¹

2023

J Cardiovasc Aging

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Protein homeostasis, the balance between protein synthesis and degradation, requires the clearance of misfolded and aggregated proteins and is therefore considered to be an essential aspect of establishing a physiologically effective proteome. Aging alters this balance, termed "proteostasis", resulting in the progressive accumulation of misfolded and aggregated proteins. Defective proteostasis leads to the functional deterioration of diverse regulatory processes during aging and is implicated in the etiology of multiple pathological conditions underlying a variety of neurodegenerative diseases and in age-dependent cardiovascular disease. Detergent-insoluble protein aggregates have been reported by us in both aged and hypertensive hearts. The protein constituents were found to overlap with protein aggregates seen in neurodegenerative diseases such as Alzheimer's disease. Therefore, targeting these protein components of aggregates may be a promising therapeutic strategy for cardiovascular pathologies associated with aging, ischemia, and/or hypertension.

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CB‐0821, a novel CC chemokine receptor 5 (CCR5) inhibitor with improved binding efficacy proposed as anti‐HIV candidate: Computational and in vitro approach

Kumar

2024

Biotech and App Biochem

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The CC chemokine receptor 5 (CCR5) serves a pivotal role in human immunodeficiency virus 1 (HIV‐1) infection by acting as a co‐receptor and facilitating the binding of the viral envelope glycoprotein (env). Maraviroc (MVC), a Food and Drug Administration‐approved monocarboxylic acid amide, is one of the CCR5 inhibitors employed in HIV treatment. Despite the existence of approved drugs, the emergence of drug resistance underscores the necessity for novel compounds to combat resistance and enhance therapeutic efficacy. In this study, CB‐0821, identified from the ChemBridge library, emerged as a promising CCR5 inhibitor. Molecular dynamics simulations indicate comparable dynamic properties for CB‐0821 and MVC. In silico comparisons with other CCR5 inhibitors emphasize CB‐0821's superior binding affinity, positioning it as a potential lead compound. Evaluations of the dissociation constant (Ki) and absorption, distribution, metabolism, and excretion predictions suggest CB‐0821 as a well‐tolerated drug. Furthermore, the dose‐dependent inhibition of CCR5 by CB‐0821 in Peripheral blood mononuclear cells (PBMCs) (ranging from 10 to 200 nM) demonstrates efficacy, coupled with nontoxicity to Vero cells at concentrations up to 500 nM. These results underscore the potential of CB‐0821 in HIV antiviral therapy, calling for additional preclinical validations before advancing to clinical considerations.

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Insilco and Invitro approaches identify novel dual PI3K/AKT pathway inhibitors to control acute myeloid leukemia cell proliferations

Cited by 15 publications

References 23 publications

Computational modeling and in vitro evaluation identified natural product—Z218 as a novel Janus kinase 2 (JAK2) inhibitor to combat β‐thalassemia

Computational modeling and in vitro evaluation identified natural product—Z218 as a novel Janus kinase 2 (JAK2) inhibitor to combat β‐thalassemia

ASGR1 and cholesterol: connecting the dots

CB‐0821, a novel CC chemokine receptor 5 (CCR5) inhibitor with improved binding efficacy proposed as anti‐HIV candidate: Computational and in vitro approach

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