Multi-dimensional structural footprint identification for the design of potential scaffolds targeting METTL3 in cancer treatment from natural compounds

Issahaku, Abdul Rashid; Mncube, Samukelisiwe Minenhle; Agoni, Clement; Kwofie, Samuel K.; Alahmdi, Mohammed Issa; Abo‐Dya, Nader E.; Sidhom, Peter A.; Tawfeek, Ahmed M.; Mukelabai, Namutula; Soremekun, Opeyemi; Soliman, Mahmoud E. S.

doi:10.1007/s00894-023-05516-5

Cited by 4 publications

(5 citation statements)

References 119 publications

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“…These candidates exhibit more negative free energy than STM2457. The in silico analysis suggested that these compounds possess drug‐like properties and lower toxicity compared to STM2457 154 . It is important to note that while the computational methods provided valuable insights into the candidates' properties, wet‐lab experiments are yet to be conducted to validate their activity in vitro or in vivo.…”

Section: Therapeutic Potentialmentioning

confidence: 99%

“…AML, osteosarcoma [152] Analogues and derivatives of adenosines [151] SANCDB0370, SANCDB0867, and SANCDB1033 [154] Quercetin Efficiently inhibits the viability of MIA PaCa-2 and Huh7 tumour cells.…”

Section: Cpb-564mentioning

confidence: 99%

“…Virtual screening of 1012 South African natural products led to the identification of three candidates, SANCDB0370, SANCDB0867, and SANCDB1033, derived from Buddleja salviifolia , Croton gratissimus , and Struthiola argentea , respectively. 154 These candidates exhibit more negative free energy than STM2457. The in silico analysis suggested that these compounds possess drug‐like properties and lower toxicity compared to STM2457.…”

Section: Therapeutic Potentialmentioning

confidence: 99%

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Targeting RNA modifications with pharmacological agents: New frontiers in cancer therapy

Guan,

Wong

2024

Cancer Medicine

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The N6‐methyladenosine (m6A) RNA modification has gained significant prominence as a new layer of regulatory mechanism that governs gene expression. Over the past decade, various m6A regulators responsible for introducing, eliminating, and recognising RNA methylation have been identified. Notably, these m6A regulators often exhibit altered expression patterns in cancer, occasionally offering prognostic value. Nonetheless, the complex roles of these regulators in human cancer pathology remain enigmatic, with conflicting outcomes reported in different studies.In recent years, a multitude of inhibitors and activators targeting m6A regulators have been reported. Several of these compounds have demonstrated promising efficacy in both in vitro and in vivo cancer models. These findings collectively underscore the dynamic landscape of m6A regulation in cancer biology, revealing its potential as a therapeutic target and prognostic indicator.

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Section: Therapeutic Potentialmentioning

confidence: 99%

Section: Cpb-564mentioning

confidence: 99%

Section: Therapeutic Potentialmentioning

confidence: 99%

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Targeting RNA modifications with pharmacological agents: New frontiers in cancer therapy

Guan,

Wong

2024

Cancer Medicine

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“…The changes in conformational dynamics of METTL3 upon the flavonoids binding is akin to STM2457 as reported by Abdul et al, wherein the compound which had demonstrated high efficacy in in vivo studies, induced stability with reduction in residual fluctuations of METTL3. [85] As such, the perturbations exhibited by these compounds further indicate their potential to therapeutically inhibit METTL3.…”

Section: Potential Anti-mttl3 Flavonoids Perturb the Global Mettl3 Co...mentioning

confidence: 99%

“…This approach has been useful at the early stages of drug discovery to screen large libraries of compounds for potential inhibitors through the exhibited docking scores. [85][86][87] This approach eliminates tentative binders from putative binders thus facilitating the drug discovery process. As such, the retrieved and processed flavonoids were then virtually screened using the two protocols to generate consensus.…”

Section: Structure Based Virtual Screening Of Flavonoidsmentioning

confidence: 99%

Leveraging Flavonoids as Potential Inhibitors of METTL3 in Combating Cancer: A Combined Structure‐Based Drug Design and DFT Approach

Abo‐Dya,

Issahaku

2023

ChemistrySelect

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Methyltransferase‐like 3 (METTL3) serves as a primary catalytic enzyme within the N6‐ methyladenosine (m6 A) methyltransferase system, playing a crucial role in various biological processes. However, its involvement in the pathogenesis of several cancers, have been well documented. The pursuit of small molecule inhibitors to counteract the cancer‐promoting effects of METTL3 has gained considerable momentum; however, no approved drugs are available. In this study, we employed computational techniques, including structure‐based virtual screening, consensus molecular docking, Density Function Theory calculations and MMPBSA energy profiling to identify potential METTL3 inhibitors from flavonoids. ST024026, ST99039 and ST4135876 were identified as promising candidates for METTL3 inhibition, as indicated by their favorable docking scores and robust energy profiles. Notably, their binding interactions were characterized by strong hydrogen bonds and hydrophobic contacts, ensuring high stability within the METTL3 binding site. Furthermore, these compounds exhibited favorable physicochemical properties and ADME characteristics, coupled with minimal toxicity. Notably, their binding induced conformational changes in the protein, underscoring their potential as METLL3 inhibitors. These findings highlight the selected flavonoids as potential novel entry inhibitors subject to modifications and optimizations. To advance this line of research, additional biochemical testing and experimental validation are warranted to facilitate the development of highly selective and effective METTL3 inhibitors.

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Sulfaquinoxaline-Derived Schiff Bases: Synthesis, Characterization, Biological Profiling, and Computational Modeling

Wajid,

Uzair,

Muhammad

et al. 2024

Journal of Molecular Structure

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Multi-dimensional structural footprint identification for the design of potential scaffolds targeting METTL3 in cancer treatment from natural compounds

Cited by 4 publications

References 119 publications

Targeting RNA modifications with pharmacological agents: New frontiers in cancer therapy

Targeting RNA modifications with pharmacological agents: New frontiers in cancer therapy

Leveraging Flavonoids as Potential Inhibitors of METTL3 in Combating Cancer: A Combined Structure‐Based Drug Design and DFT Approach

Sulfaquinoxaline-Derived Schiff Bases: Synthesis, Characterization, Biological Profiling, and Computational Modeling

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