Cardiovascular diseases (CVDs) are the leading cause of death globally, attributed to a complex etiology involving metabolic, genetic, and protein-related factors. Lipoprotein(a) (Lp(a)), identified as a genetic risk factor, exhibits elevated levels linked to an increased risk of cardiovascular diseases. The lipoprotein(a) kringle domains have recently been identified as a potential target for the treatment of CVDs, in this study we utilized a fragment-based drug design approach to design a novel, potent, and safe inhibitor for lipoprotein(a) kringle domain. With the use of fragment library (61,600 fragments) screening, combined with analyses such as MM/GBSA, molecular dynamics simulation (MD), and principal component analysis, we successfully identified molecules effective against the kringle domains of Lipoprotein(a). The hybridization process (Breed) of the best fragments generated a novel 249 hybrid molecules, among them 77 exhibiting superior binding affinity (≤ -7 kcal/mol) compared to control AZ-02 (-6.9 kcal/mol), Importantly, the top ten molecules displayed high similarity to the control AZ-02. Among the top ten molecules, BR1 exhibited the best docking energy (-11.85 kcal/mol ), and higher stability within the protein LBS site, demonstrating the capability to counteract the pathophysiological effects of lipoprotein(a) [Lp(a)]. Additionally, principal component analysis (PCA) highlighted a similar trend of motion during the binding of BR1 and the control compound (AZ-02), limiting protein mobility and reducing conformational space. Moreover, ADMET analysis indicated favorable drug-like properties, with BR1 showing minimal violations of Lipinski's rules. Overall, the identified compounds hold promise as potential therapeutics, addressing a critical need in cardiovascular medicine. Further preclinical and clinical evaluations are needed to validate their efficacy and safety, potentially ushering in a new era of targeted therapies for CVDs.

2023-05-18·Plants (Basel, Switzerland)

Argentatin Content in Guayule Leaves (Parthenium argentatum A. Gray).

Article

作者: De la Cruz-Morcillo, Miguel Ángel ; García-Martínez, María Mercedes ; Latorre, Guayente ; Zalacain, Amaya ; Carrión, María Engracia ; Gallego, Beatriz ; Carmona, Manuel

Approximately one-third of the waste biomass from the cultivation of guayule (Parthenium argentatum A. Gray) for natural rubber production is leaf tissue; however, whether it can be valorized is not known. Guayulins and argentatins are potential high-value products that can be recovered from guayule resin during rubber/latex processing. Argentatins are highly abundant in guayule stem resin; however, unlike the guayulins, their occurrence in leaves has not been investigated. The present study determined the content of argentatins and isoargentatins A and B in the leaves of a pure guayule accession (R1040) and two hybrids (CAL-1 and AZ-2) under conditions of irrigation and non-irrigation. The resin content in leaves was ~10%, which provides a suitable starting point for economic exploitation. The highest production of argentatins occurred in plants under irrigation, with yields of 4.2 and 3.6 kg ha^-1 for R1040 and AZ-2, respectively. The R1040 accession had the highest percentage of resin and the greatest total argentatin content (24.5 g kg^-1 dried leaf), principally due to the abundance of argentatin A. Contrastingly, CAL-1 consistently showed the lowest argentatin content based on dried leaf weight and production (0.6 kg ha^-1). The substantial abundance of argentatins in guayule leaves suggests the potential for future exploitation.

2022-12-01·Molecular Diversity3区 · 化学

DNA binding and cleavage, BRCA1 gene interaction, antiglycation and anticancer studies of transition metal complexes of sulfonamides

3区 · 化学

Article

作者: Asiri, Abdullah M ; Akhtar, Arusa ; Arshad, Muhammad Nadeem ; Danish, Muhammad ; Asif, Awais

A series of 4-((4-methylphenylsulfonamido)methyl)cyclohexanecarboxylic acid (NaMSCCA) transition metal complexes [Cu(II), Zn(II), Ni(II), Mn(II), and Co(II)] have been synthesized by precipitation method. The characterization was done by physical techniques, FT-IR spectroscopy, mass spectrometry, and NMR spectroscopy. The molecular structures of nickel (II) AZ-3 and cobalt (II) AZ-5 complexes were determined by the X-ray diffraction technique and found to crystallize in the triclinic space group P-1. The coordination geometry around the central nickel (AZ-3) and cobalt (AZ-5) atoms was square planar bipyramidal. Molecular docking was performed with duplex DNA of sequence d(CGCGAATTCGCG)₂ DNA to determine the probable binding mode of compounds. Then these synthesized compounds were used to perform DNA cleavage activity through the agarose gel electrophoresis method. Among the compounds, compounds AZ-1 and AZ-2 exhibited good nuclease activity. The DNA sequence of breast-cancer suppressor gene 1 (BRCA1) was amplified through PCR and interaction studies of compounds AZ-1 and AZ-2 were performed through gel electrophoresis and fluorescence emission spectroscopy. The expression analysis of the BRCA1 gene was also performed to quantify the expression relative fold change (2^-(∆∆CT)) after treatment with compounds. All synthesized compounds were evaluated for their antioxidant and antiglycation activities and AZ-2 exhibited excellent results. The molecular docking study of these compounds was performed against the protein structure of advanced glycation end products to support the experimental results. Anticancer activity of compounds was performed through MTT assay. Copper and zinc complexes depicted the highest anticancer activity against human breast adenocarcinoma (MCF7) and human corneal epithelial cell (HCEC) cell lines.

100 项与 AZ-02 相关的药物交易

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