Dataset Information

A pocket-based 3D molecule generative model fueled by experimental electron density.

ABSTRACT: We report for the first time the use of experimental electron density (ED) as training data for the generation of drug-like three-dimensional molecules based on the structure of a target protein pocket. Similar to a structural biologist building molecules based on their ED, our model functions with two main components: a generative adversarial network (GAN) to generate the ligand ED in the input pocket and an ED interpretation module for molecule generation. The model was tested on three targets: a kinase (hematopoietic progenitor kinase 1), protease (SARS-CoV-2 main protease), and nuclear receptor (vitamin D receptor), and evaluated with a reference dataset composed of over 8000 compounds that have their activities reported in the literature. The evaluation considered the chemical validity, chemical space distribution-based diversity, and similarity with reference active compounds concerning the molecular structure and pocket-binding mode. Our model can generate molecules with similar structures to classical active compounds and novel compounds sharing similar binding modes with active compounds, making it a promising tool for library generation supporting high-throughput virtual screening. The ligand ED generated can also be used to support fragment-based drug design. Our model is available as an online service to academic users via https://edmg.stonewise.cn/#/create .

SUBMITTER: Wang L

PROVIDER: S-EPMC9448726 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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A pocket-based 3D molecule generative model fueled by experimental electron density.

Wang Lvwei L Bai Rong R Shi Xiaoxuan X Zhang Wei W Cui Yinuo Y Wang Xiaoman X Wang Cheng C Chang Haoyu H Zhang Yingsheng Y Zhou Jielong J Peng Wei W Zhou Wenbiao W Huang Bo B

Scientific reports 20220906 1

We report for the first time the use of experimental electron density (ED) as training data for the generation of drug-like three-dimensional molecules based on the structure of a target protein pocket. Similar to a structural biologist building molecules based on their ED, our model functions with two main components: a generative adversarial network (GAN) to generate the ligand ED in the input pocket and an ED interpretation module for molecule generation. The model was tested on three targets ...[more]

PMID: 36068257

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Project description:BackgroundThis study aims to capture the 3D shape of the human skull in a healthy paediatric population (0-4 years old) and construct a generative statistical shape model.MethodsThe skull bones of 178 healthy children (55% male, 20.8 ± 12.9 months) were reconstructed from computed tomography (CT) images. 29 anatomical landmarks were placed on the 3D skull reconstructions. Rotation, translation and size were removed, and all skull meshes were placed in dense correspondence using a dimensionless skull mesh template and a non-rigid iterative closest point algorithm. A 3D morphable model (3DMM) was created using principal component analysis, and intrinsically and geometrically validated with anthropometric measurements. Synthetic skull instances were generated exploiting the 3DMM and validated by comparison of the anthropometric measurements with the selected input population.ResultsThe 3DMM of the paediatric skull 0-4 years was successfully constructed. The model was reasonably compact - 90% of the model shape variance was captured within the first 10 principal components. The generalisation error, quantifying the ability of the 3DMM to represent shape instances not encountered during training, was 0.47 mm when all model components were used. The specificity value was <0.7 mm demonstrating that novel skull instances generated by the model are realistic. The 3DMM mean shape was representative of the selected population (differences <2%). Overall, good agreement was observed in the anthropometric measures extracted from the selected population, and compared to normative literature data (max difference in the intertemporal distance) and to the synthetic generated cases.ConclusionThis study presents a reliable statistical shape model of the paediatric skull 0-4 years that adheres to known skull morphometric measures, can accurately represent unseen skull samples not used during model construction and can generate novel realistic skull instances, thus presenting a solution to limited availability of normative data in this field.

Dataset Information

A pocket-based 3D molecule generative model fueled by experimental electron density.

Publications

A pocket-based 3D molecule generative model fueled by experimental electron density.

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