Discovery of microtubule stabilizers with novel scaffold structures based on virtual screening, biological evaluation, and molecular dynamics simulation

Mao, Jun; Luo, Qingzhi; Zhang, Hongrui; Zheng, Xizhong; Shen, Chen; Qi, Hua-Zhao; Hu, Mei-Ling; Zhang, Hui

doi:10.1016/j.cbi.2021.109784

Cited by 3 publications

(1 citation statement)

References 54 publications

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“…To minimize the cost and time for a drug development process, computer-aided drug design (CADD) is one of the extensively used methods ( Li et al, 2009 ; Lima et al, 2018 ). This method employs in silico techniques which allow us to analyze a large chemical library in a short period of time to identify the hits based on their interaction with the target protein ( Mao et al, 2021 ). It also allows analyzing the stability of the protein–ligand complex using simulation tools and prediction of the drug-like properties.…”

Section: Introductionmentioning

confidence: 99%

Target-Based Virtual Screening of Natural Compounds Identifies a Potent Antimalarial With Selective Falcipain-2 Inhibitory Activity

et al. 2022

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We employed a comprehensive approach of target-based virtual high-throughput screening to find potential hits from the ZINC database of natural compounds against cysteine proteases falcipain-2 and falcipain-3 (FP2 and FP3). Molecular docking studies showed the initial hits showing high binding affinity and specificity toward FP2 were selected. Furthermore, the enzyme inhibition and surface plasmon resonance assays were performed which resulted in a compound ZINC12900664 (ST72) with potent inhibitory effects on purified FP2. ST72 exhibited strong growth inhibition of chloroquine-sensitive (3D7; EC50 = 2.8 µM) and chloroquine-resistant (RKL-9; EC50 = 6.7 µM) strains of Plasmodium falciparum. Stage-specific inhibition assays revealed a delayed and growth defect during parasite growth and development in parasites treated with ST72. Furthermore, ST72 significantly reduced parasite load and increased host survival in a murine model infected with Plasmodium berghei ANKA. No Evans blue staining in ST72 treatment indicated that ST72 mediated protection of blood–brain barrier integrity in mice infected with P. berghei. ST72 did not show any significant hemolysis or cytotoxicity against human HepG2 cells suggesting a good safety profile. Importantly, ST72 with CQ resulted in improved growth inhibitory activity than individual drugs in both in vitro and in vivo studies.

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Section: Introductionmentioning

confidence: 99%

Target-Based Virtual Screening of Natural Compounds Identifies a Potent Antimalarial With Selective Falcipain-2 Inhibitory Activity

et al. 2022

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Discovery of novel microtubule stabilizers targeting taxane binding site by applying molecular docking, molecular dynamics simulation, and anticancer activity testing

Zhang

Mao

et al. 2022

Bioorganic Chemistry

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Computational Approaches to the Rational Design of Tubulin-Targeting Agents

et al. 2023

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Microtubules are highly dynamic polymers of α,β-tubulin dimers which play an essential role in numerous cellular processes such as cell proliferation and intracellular transport, making them an attractive target for cancer and neurodegeneration research. To date, a large number of known tubulin binders were derived from natural products, while only one was developed by rational structure-based drug design. Several of these tubulin binders show promising in vitro profiles while presenting unacceptable off-target effects when tested in patients. Therefore, there is a continuing demand for the discovery of safer and more efficient tubulin-targeting agents. Since tubulin structural data is readily available, the employment of computer-aided design techniques can be a key element to focus on the relevant chemical space and guide the design process. Due to the high diversity and quantity of structural data available, we compiled here a guide to the accessible tubulin-ligand structures. Furthermore, we review different ligand and structure-based methods recently used for the successful selection and design of new tubulin-targeting agents.

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Discovery of microtubule stabilizers with novel scaffold structures based on virtual screening, biological evaluation, and molecular dynamics simulation

Cited by 3 publications

References 54 publications

Target-Based Virtual Screening of Natural Compounds Identifies a Potent Antimalarial With Selective Falcipain-2 Inhibitory Activity

Target-Based Virtual Screening of Natural Compounds Identifies a Potent Antimalarial With Selective Falcipain-2 Inhibitory Activity

Discovery of novel microtubule stabilizers targeting taxane binding site by applying molecular docking, molecular dynamics simulation, and anticancer activity testing

Computational Approaches to the Rational Design of Tubulin-Targeting Agents

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