Current Medicinal Chemistry - Online First
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Discovery of 5-(Substituted Phenyl)-2-aryl Benzimidazole Derivatives as SIRT1 Activators: Their Design, in silico Studies, Synthesis, and in vitro Evaluation
Authors: Shilpi Chauhan, Ashwani Kumar, Rajnish Kumar and Deepika SainiAvailable online: 10 October 2024More LessAimSilent information regulator two homologue one (SIRT1) is an emerging target for managing metabolic disorders. This study aimed to synthesize novel 5-(substituted phenyl)-2-aryl benzimidazole derivatives and evaluate them for SIRT1 activation.
MethodsThe compounds were designed according to the findings of the QSAR models framed in our previous studies. Molecular docking and dynamics studies were also performed to explore the interactions of designed compounds with the active site of the SIRT1 enzyme using AutoDock Vina and Schrödinger Maestro version 11.8.012, respectively. Compounds with good binding affinity were synthesized by Suzuki-Miyaura cross-coupling and spectrally characterized. The molecules were evaluated for their in vitro SIRT1 activation properties using a fluorescent screening kit. Based on the results of in vitro assay, a structure-activity relationship was established. SwissADME was employed to calculate the pharmacokinetics characteristics of the synthesized molecules.
ResultsThe molecular docking studies revealed that all the activators were effectively docked in the catalytic active site. All compounds demonstrated interactions with important amino acids like Glu230 and Arg446. In molecular dynamics simulations, the root mean square deviation (RMSD) of compound 5m and protein SIRT1 remained stable, i.e., below 3mm. Compound 5m, 4-(2-(3,4-dihydroxy-5-nitrophenyl)-1H-benzo[d]imidazol-5-yl)benzaldehyde, was the most potent compound with an EC50 value of 0.006 mM (±0.001) and maximum activation of 240.5%. All the synthesized compounds had acceptable theoretical ADME profiles, and drug-likeness properties complied with Lipinski’s rule.
ConclusionAccording to the findings, synthesized compounds may be viable leads for SIRT1 activators and may be used to advance preclinical in vivo research utilizing animal models.
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Targeting Fructosamine Oxidase (Amadoriase II) in Aspergillus fumigatus: Comprehensive Virtual Screening, ADMET Analysis, and Molecular Dynamics Simulation of Triazole Derivatives
Available online: 12 September 2024More LessIntroductionAspergillus fumigatus, a significant fungal pathogen, poses a threat to human health, especially in immunocompromised individuals. Addressing the need for novel antifungal strategies, this study employs virtual screening to identify potential inhibitors of Fructosamine oxidase, also known as Amadoriase II, a crucial enzyme in A. fumigatus (PDB ID: 3DJE).
MethodVirtual screening of 81,197 triazole derivatives was subjected to computational analysis, aiming to pinpoint molecules with high binding affinity to the active site of Fructosamine oxidase. Subsequently, an in-depth ADMET analysis assessed the pharmacokinetic properties of lead compounds, ensuring their viability for further development. Molecular dynamics simulations were performed to evaluate the stability of top-ranked compounds over time.
ResultsThe results unveil a subset of triazole derivatives displaying promising interactions, suggesting their potential as inhibitors for further investigation.
ConclusionThis approach contributes to the development of targeted antifungal agents, offering a rational starting point for experimental validation and drug development against Aspergillus fumigatus infections.
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Mitochondrial DNA Mutations in Colorectal Cancer Stem Cells: Implications for Tumor Dynamics and Therapeutic Strategies
Available online: 11 September 2024More LessThis review offers an in-depth analysis of mitochondrial DNA (mtDNA) mutations in colorectal cancer stem cells (CSCs), emphasizing their significant impact on tumor dynamics and potential therapeutic strategies. CSCs are a special subpopulation due to their unique capabilities for self-renewal, differentiation, and resistance to conventional therapies. Given that CSCs significantly differ from other tumor cell subpopulations, particularly in their metabolic properties, and considering that colorectal cancer is a malignancy characterized by mitochondrial dysfunction, this review aims to put together existing data on the differences in the mitochondrial genome of CSCs compared to other colorectal tumor cell subpopulations. Additionally, the review seeks to explore the potential roles of these differences and to identify new ideas for therapeutic strategies. Key topics include the identification and properties of CSCs in colorectal cancer, the distinctive features of the mitochondrial genome, and the functional consequences of mtDNA mutations. The review hypothesizes that CSCs rely on well-functioning mitochondria for crucial aspects like energy production; yet, mtDNA mutations can lead to mitochondrial dysfunction, altering CSC characteristics and influencing cancer progression. The article discusses emerging therapeutic approaches targeting mitochondrial function in colorectal CSCs and highlights the need for advanced research, including the development of preclinical models and exploration of targeted therapies, to improve the understanding and treatment of colorectal cancer.
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