Identification of Potential WSB1 Inhibitors by AlphaFold Modeling, Virtual Screening, and Molecular Dynamics Simulation Studies

Weng, Ye; Pan, Chenghao; Shen, Zheyuan; Chen, Sikang; Xu, Lei; Dong, Xiaowu; Chen, Jing

doi:10.1155/2022/4629392

Cited by 10 publications

(8 citation statements)

References 51 publications

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“…Performance is likely to be limited by the availability of an adjacent holo template in the PDB. Chen et al performed short MD simulations prior to virtual screening with docking to identify potential WSB1 inhibitors. Ray and co-workers explored the retrospective FEP performance on AF2 models, using Schrödinger’s FEP+ package, together with a popular benchmark data set for evaluating the performance of FEP implementations.…”

Section: Introductionmentioning

confidence: 99%

Benchmarking Refined and Unrefined AlphaFold2 Structures for Hit Discovery

Zhang

Vass²,

Shi

et al. 2023

J. Chem. Inf. Model.

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The recently developed AlphaFold2 (AF2) algorithm predicts proteins’ 3D structures from amino acid sequences. The open AlphaFold protein structure database covers the complete human proteome. Using an industry-leading molecular docking method (Glide), we investigated the virtual screening performance of 37 common drug targets, each with an AF2 structure and known holo and apo structures from the DUD-E data set. In a subset of 27 targets where the AF2 structures are suitable for refinement, the AF2 structures show comparable early enrichment of known active compounds (avg. EF 1%: 13.0) to apo structures (avg. EF 1%: 11.4) while falling behind early enrichment of the holo structures (avg. EF 1%: 24.2). With an induced-fit protocol (IFD-MD), we can refine the AF2 structures using an aligned known binding ligand as the template to improve the performance in structure-based virtual screening (avg. EF 1%: 18.9). Glide-generated docking poses of known binding ligands can also be used as templates for IFD-MD, achieving similar improvements (avg. EF 1% 18.0). Thus, with proper preparation and refinement, AF2 structures show considerable promise for in silico hit identification.

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Section: Introductionmentioning

confidence: 99%

Benchmarking Refined and Unrefined AlphaFold2 Structures for Hit Discovery

Zhang

Vass²,

Shi

et al. 2023

J. Chem. Inf. Model.

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“…This docking study ccap targets and selects active sites for targeted docking. PyMOL 2.3.0 was utilized to visualize the processed proteins and docking results [39,40].…”

Section: Methodsmentioning

confidence: 99%

Functional validation of squalene epoxidase in triterpenes biosynthesis in Poria cocos by molecular docking and CRISPR-Cas9 gene editing

Liu

Xie

et al. 2023

Preprint

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Background Squalene epoxidase is one of the rate-limiting enzymes in the biosynthetic pathway of membrane sterols and triterpenoids. The enzyme catalyzes the formation of oxidized squalene, which is a common precursor of sterols and triterpenoids. In recent years, CRISPR/Cas9 gene editing technology has emerged and other functional genes in the Poria cocos triterpene synthesis pathway have been studied; PcSE has not been reported. Results In this study, the squalene epoxidase gene (PcSE) was evaluated in Poria cocos. Molecular docking between PcSE and squalene was performed and the active amino acids were identified. sgRNA sequences were designed based on the active site residues. In vivo verification of PcSE function was performed using a PEG-mediated protoplast transformation approach. The effect on triterpene synthesis in P. cocos was consistent with the results from ultra-high-performance liquid chromatography-quadruplex time-of-flight-double mass spectrometry (UHPLC-QTOF-MS/MS) analysis. Which showed that deletion of PcSE inhibited triterpene synthesis. Conclusions A gene editing system based on molecular docking was successfully constructed to demonstrate that PcSE functions as a house squalene cyclooxygenase, which provides a basis for further studies on the heterologous biosynthesis of P. cocos secondary metabolites.

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“…They concluded that the limitations in benchmarking are not due to the AlphaFold structures itself, but to the methods to accurately model the protein-ligand interactions [27]. Other studies have identified potential inhibitors of WD40 repeat and SOCS box containing 1 protein (WSB1), a clinically relevant drug target, by means of AlphaFold and virtual screening approaches [28].…”

Section: Structural Data Determinationmentioning

confidence: 99%

Comprehensive Survey of Consensus Docking for High-Throughput Virtual Screening

et al. 2022

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The rapid advances of 3D techniques for the structural determination of proteins and the development of numerous computational methods and strategies have led to identifying highly active compounds in computer drug design. Molecular docking is a method widely used in high-throughput virtual screening campaigns to filter potential ligands targeted to proteins. A great variety of docking programs are currently available, which differ in the algorithms and approaches used to predict the binding mode and the affinity of the ligand. All programs heavily rely on scoring functions to accurately predict ligand binding affinity, and despite differences in performance, none of these docking programs is preferable to the others. To overcome this problem, consensus scoring methods improve the outcome of virtual screening by averaging the rank or score of individual molecules obtained from different docking programs. The successful application of consensus docking in high-throughput virtual screening highlights the need to optimize the predictive power of molecular docking methods.

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Identification of Potential WSB1 Inhibitors by AlphaFold Modeling, Virtual Screening, and Molecular Dynamics Simulation Studies

Cited by 10 publications

References 51 publications

Benchmarking Refined and Unrefined AlphaFold2 Structures for Hit Discovery

Benchmarking Refined and Unrefined AlphaFold2 Structures for Hit Discovery

Functional validation of squalene epoxidase in triterpenes biosynthesis in Poria cocos by molecular docking and CRISPR-Cas9 gene editing

Comprehensive Survey of Consensus Docking for High-Throughput Virtual Screening

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