Docking Studies for Multi-Target Drugs

Scotti, Luciana; Mendonça, Francisco Jaime Bezerra; Ishiki, Hamilton Mitsugu; Ribeiro, Frederico Fávaro; Singla, Rajeev K.; Barbosa-Filho, José Maria; Silva, Marcelo Sobral da

doi:10.2174/1389450116666150825111818

Cited by 45 publications

(21 citation statements)

References 132 publications

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“…Cellular target identification is a crucial prerequisite for clarifying biological mechanism of candidate drug. Reverse virtual screening which is based on “lock-key principle” of molecular docking is an effective method for cellular target identification [ 28 ]. The interaction between ligand and target protein is a process of molecular recognition, including electrostatic interaction, hydrogen bonding interaction, hydrophobic interaction, and van der Waals interaction.…”

Section: Discussionmentioning

confidence: 99%

Costunolide Plays an Anti-Neuroinflammation Role in Lipopolysaccharide-Induced BV2 Microglial Activation by Targeting Cyclin-Dependent Kinase 2

Liu

Feng

et al. 2020

Molecules

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Hyperactivation of microglia in the brain is closely related to neuroinflammation and leads to neuronal dysfunction. Costunolide (CTL) is a natural sesquiterpene lactone with wide pharmacological activities including anti-inflammation and antioxidation. In this study, we found that CTL significantly inhibited the production of inflammatory mediators including nitric oxide, IL-6, TNF-α, and PGE2 in lipopolysaccharide (LPS)-stimulated BV2 microglia. Moreover, CTL effectively attenuated IKKβ/NF-κB signaling pathway activation. To identify direct cellular target of CTL, we performed high-throughput reverse virtual screening assay using scPDB protein structure library, and found cyclin-dependent kinase 2 (CDK2) was the most specific binding protein for CTL. We further confirmed the binding ability of CTL with CDK2 using cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) assays. Surface plasmon resonance analysis also supported that CTL specifically bound to CDK2 with a dissociation constant at micromole level. Furthermore, knocking down CDK2 obviously reversed the anti-inflammation effect of CTL via AKT/IKKβ/NF-κB signaling pathway on BV-2 cells. Collectively, these results indicate that CTL inhibits microglia-mediated neuroinflammation through directly targeting CDK2, and provide insights into the role of CDK2 as a promising anti-neuroinflammation therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Costunolide Plays an Anti-Neuroinflammation Role in Lipopolysaccharide-Induced BV2 Microglial Activation by Targeting Cyclin-Dependent Kinase 2

Liu

Feng

et al. 2020

Molecules

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“…To the best of our knowledge, this is the first time that LC-Q-TOF-MS and UF-HPLC-MD have been integrated in the identification and screening of major bioactive components from SMD. The LC-Q-TOF-MS technique could improve the fast detection of chemical compounds, while UF-HPLC-MD supports an approach for the recognition of bioactive ligands of HSA, predicting their binding sites and illustrating more information about the interaction mechanisms between receptor and active ligands [ 22 ]. The present study illustrates and explains the practical application of the bioactive compounds of SMD for the clinical treatment of gastrointestinal diseases.…”

Section: Introductionmentioning

confidence: 99%

Rapid Investigation and Screening of Bioactive Components in Simo Decoction via LC-Q-TOF-MS and UF-HPLC-MD Methods

Cheng

Wang

et al. 2018

Molecules

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Simo decoction (SMD), as a traditional medicine, is widely used in the treatment of gastrointestinal dysmotility in China. In this study, a combined method of liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS) and ultrafiltration high-performance liquid chromatography molecular docking (UF-HPLC-MD) was efficiently employed to identify and screen bioactive ingredients in SMD. Ninety-four major constituents were identified or tentatively characterized by comparing their retention times and mass spectra with standards or literature data by using LC-Q-TOF-MS, and the ascription of those compounds were classified for the first time. Among them, 13 bioactive ingredients, including norisoboldine, eriocitrin, neoeriocitrin, narirutin, hesperidin, naringin, neohesperidin, hesperitin-7-O-glucoside, linderane, poncirin, costunolide, nobiletin, and tangeretin, were primarily identified as the human serum albumin (HSA) ligands at a range of docking scores from −29.7 to −40.6 kJ/mol by UF-HPLC-MD. The results indicate the systematic identification and screening of HSA ligands from Simo decoction guided by LC-Q-TOF-MS and UF-HPLC-MD represents a feasible and efficient method that could be extended for the identification and screening of other bioactive ingredients from natural medicines.

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“…It has been acknowledged that cancer is caused by a set of driver mutations. In this regard, it is of great significance to: (1) identify and validate key mutant genes and proteins in cancers as new targets; (2) identify patients most likely and unlikely to benefit from certain targeted therapies; (3) evaluate the mechanism of mutation-driven drug resistance. In past decades, several key mutations which influence drug sensitivity have been identified in various cancers.…”

Section: Discussionmentioning

confidence: 99%

“…Targeted therapies usually present with high selectivity, target precisely to specific gene or protein, and exert a biological function with minimal side effects (1), which has distinguished them from most conventional non-specific chemotherapeutic drugs. Targeted therapy has thus been regarded as the biggest success in the treatment of cancer in the past few decades.…”

Section: Introductionmentioning

confidence: 99%

Identification of Genetic Mutations in Cancer: Challenge and Opportunity in the New Era of Targeted Therapy

Jin¹,

Wu²,

Yin³

et al. 2019

Front. Oncol.

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The introduction of targeted therapy is the biggest success in the treatment of cancer in the past few decades. However, heterogeneous cancer is characterized by diverse molecular alterations as well as multiple clinical profiles. Specific genetic mutations in cancer therapy targets may increase drug sensitivity, or more frequently result in therapeutic resistance. In the past 3 years, several novel targeted therapies have been approved for cancer treatment, including drugs with new targets (i.e., anti-PD1/PDL1 therapies and CDK4/6 inhibitors), mutation targeting drugs (i.e., the EGFR T790M targeting osimertinib), drugs with multiple targets (i.e., the EGFR/HER2 dual inhibitor neratinib) and drug combinations (i.e., encorafenib/binimetinib and dabrafenib/trametinib). In this perspective, we focus on the most up-to-date knowledge of targeted therapy and describe how genetic mutations influence the sensitivity of targeted therapy, highlighting the challenges faced within this era of precision medicine. Moreover, the strategies that deal with mutation-driven resistance are further discussed. Advances in these areas would allow for more targeted and effective therapeutic options for cancer patients.

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Docking Studies for Multi-Target Drugs

Cited by 45 publications

References 132 publications

Costunolide Plays an Anti-Neuroinflammation Role in Lipopolysaccharide-Induced BV2 Microglial Activation by Targeting Cyclin-Dependent Kinase 2

Costunolide Plays an Anti-Neuroinflammation Role in Lipopolysaccharide-Induced BV2 Microglial Activation by Targeting Cyclin-Dependent Kinase 2

Rapid Investigation and Screening of Bioactive Components in Simo Decoction via LC-Q-TOF-MS and UF-HPLC-MD Methods

Identification of Genetic Mutations in Cancer: Challenge and Opportunity in the New Era of Targeted Therapy

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