Rab5B is a small monomeric G protein that regulates early endocytosis and controls signaling pathways related to cell growth, survival, and apoptosis. Dysregulation of Rab5B protein expression has been linked to the development of several cancers such as leukemia, lymphoma, kidney, prostate, ovarian, breast cancer, etc. Our research shows the first attempt to identify inhibitors that can target Rab5B GTPase. In this study, we performed molecular docking using Autodock Vina 1.5.6 and identified eight molecules with docking scores ranging from -9.8 to -10.6 kcal/mol. Thereafter, we examined the pharmacological characteristics of these compounds, and selected compounds were further analyzed for their conformational dynamics and thermodynamic stability using molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA)-based free energy calculations. Notably, our findings revealed that strychnine had the highest binding affinity to Rab5B followed by anonaine, helioxanthin, and taiwanin E, with a ΔG_bind value of -21.43, -17.11, -15.11, and -14.09 kcal/mol respectively. The binding free energy calculations showed that Van der Waals interactions are the primary contributor to the binding between Rab5B and the inhibitor. The interaction between the inhibitor and Rab5B was shown to be controlled by certain hot spot residues, including Phe45, Tyr48, Ala64, and Ala30. Overall, we believe that these findings could facilitate the exploration and development of potential hits against Rab5B, subject to optimization and further research.

2024-03-13·Journal of Agricultural and Food Chemistry

Insecticidal Activity and Molecular Target by Morphological Analysis, RNAseq, and Molecular Docking of the Aryltetralin Lignan Lactone Helioxanthin, Isolated from Taiwania flousiana Gaussen

Article

作者: Zhou, Yifeng ; Bi, Xiaoyang ; Zhou, Lijuan ; Li, Dandan ; Xu, Zuowei ; Huang, Jiguang ; Lin, Meihong

Botanical insecticides are considered an environmentally friendly approach to insect control because they are easily biodegraded and cause less environmental pollution compared to traditional chemical pesticides. In this study, we reported the insecticidal activities of the ingredients from Taiwania flousiana Gaussen (T. flousiana). Five compounds, namely helioxanthin (C1), taiwanin E (C2), taiwanin H (C3), 7,4'-dimethylamentoflavone (C4), and 7,7″-di-O-methylamentoflavone (C5), were isolated and tested against the second, third, and fourth instar larvae of Aedes aegypti. Our results indicated that all five compounds showed insecticidal activities, and helioxanthin, which is an aryltetralin lignan lactone, was the most effective with LC₅₀ values of 0.60, 2.82, and 3.12 mg/L, respectively, 48 h after application, with its activity against the second instar larvae similar to that of pyrethrin and better than that of rotenone. Further studies found that helioxanthin accumulated in the gastric cecum and the midgut and caused swelling of mitochondria with shallow matrices and fewer or disappeared crista. Additionally, our molecular mechanisms studies indicated that the significantly differentially expressed genes (DEGs) were mainly associated with mitochondria and the cuticle, among which the voltage-dependent anion-selective channel (VDAC) gene was the most down-regulated by helioxanthin, and VDAC is the potential target of helioxanthin by binding to specific amino acid residues (His 122 and Glu 147) via hydrogen bonds. We conclude that aryltetralin lignan lactone is a potential class of novel insecticides by targeting VDAC.

2023-11-15·Antimicrobial Agents and Chemotherapy

Identification of potential inhibitors of casein kinase 2 alpha of Plasmodium falciparum with potent in vitro activity

Article

作者: Moreira-Filho, José T ; Andrade, Carolina H ; Cassiano, Gustavo C ; Levandoski, João E ; Tomaz, Kaira C P ; Sunnerhagen, Per ; Tavella, Tatyana A ; Salazar-Alvarez, Luis C ; Massirer, Katlin B ; Costa, Fabio T M ; Mottin, Melina ; Borba, Joyce V B ; Clementino, Leandro C ; Almeida, Vitor M ; Sousa, Bruna K P ; Couñago, Rafael M ; Bilsland, Elizabeth ; Bourgard, Catarina

ABSTRACT Drug resistance to commercially available antimalarials is a major obstacle in malaria control and elimination, creating the need to find new antiparasitic compounds with novel mechanisms of action. The success of kinase inhibitors for oncological treatments has paved the way for the exploitation of protein kinases as drug targets in various diseases, including malaria. Casein kinases are ubiquitous serine/threonine kinases involved in a wide range of cellular processes such as mitotic checkpoint signaling, DNA damage response, and circadian rhythm. In Plasmodium , it is suggested that these protein kinases are essential for both asexual and sexual blood-stage parasites, reinforcing their potential as targets for multi-stage antimalarials. To identify new putative Pf CK2α inhibitors, we utilized an in silico chemogenomic strategy involving virtual screening with docking simulations and quantitative structure-activity relationship predictions. Our investigation resulted in the discovery of a new quinazoline molecule ( 542 ), which exhibited potent activity against asexual blood stages and a high selectivity index (>100). Subsequently, we conducted chemical-genetic interaction analysis on yeasts with mutations in casein kinases. Our chemical-genetic interaction results are consistent with the hypothesis that 542 inhibits yeast Cka1, which has a hinge region with high similarity to Pf CK2α. This finding is in agreement with our in silico results suggesting that 542 inhibits Pf CK2α via hinge region interaction.

100 项与 Helioxanthin 相关的药物交易

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