# Accurate Physical Property Predictions via Deep Learning

^{1}

^{2}

^{3}

^{*}

## Abstract

**:**

## 1. Introduction

## 2. Results

#### 2.1. Training of BCSA Model

#### 2.2. Compare with State-of-the-Art Models

#### 2.3. Predicting Other Related Physicochemical Properties

## 3. Discussion

## 4. Materials and Methods

#### 4.1. Molecular Dataset and Processing

#### 4.2. Model Building

#### 4.3. Hyperparameter Search

#### 4.4. Evaluation Metrics

## Supplementary Materials

## Author Contributions

## Funding

## Institutional Review Board Statement

## Informed Consent Statement

## Data Availability Statement

## Conflicts of Interest

## Sample Availability

## References

- Merkwirth, C.; Lengauer, T. Automatic generation of complementary descriptors with molecular graph networks. J. Chem. Inf. Modeling
**2005**, 45, 1159–1168. [Google Scholar] [CrossRef] - DiMasi, J.A.; Grabowski, H.G.; Hansen, R.W. Innovation in the pharmaceutical industry: New estimates of R&D costs. J. Health Econ.
**2016**, 47, 20–33. [Google Scholar] [PubMed][Green Version] - Mikolov, T.; Chen, K.; Corrado, G.; Dean, J. Efficient estimation of word representations in vector space. arXiv
**2013**, arXiv:1301.3781. [Google Scholar] - Pennington, J.; Socher, R.; Manning, C.D. Glove: Global vectors for word representation. In Proceedings of the 2014 Conference on Empirical Methods in Natural Language Processing (EMNLP), Doha, Qatar, 25–29 October 2014; pp. 1532–1543. [Google Scholar]
- Ling, W.; Luís, T.; Marujo, L.; Astudillo, R.F.; Amir, S.; Dyer, C.; Black, A.W.; Trancoso, I. Finding function in form: Compositional character models for open vocabulary word representation. arXiv
**2015**, arXiv:1508.02096. [Google Scholar] - Vaswani, A.; Shazeer, N.; Parmar, N.; Uszkoreit, J.; Jones, L.; Gomez, A.N.; Kaiser, Ł.; Polosukhin, I. Attention is all you need. Adv. Neural Inf. Processing Syst.
**2017**, 30, 6000–6010. [Google Scholar] - Devlin, J.; Chang, M.-W.; Lee, K.; Toutanova, K. Bert: Pre-training of deep bidirectional transformers for language understanding. arXiv
**2018**, arXiv:1810.04805. [Google Scholar] - Gers, F.A.; Schmidhuber, J.; Cummins, F. Learning to forget: Continual prediction with LSTM. Neural Comput.
**2000**, 12, 2451–2471. [Google Scholar] [CrossRef] - Sutskever, I.; Vinyals, O.; Le, Q.V. Sequence to sequence learning with neural networks. Adv. Neural Inf. Processing Syst.
**2014**, 27. [Google Scholar] - Girshick, R.; Donahue, J.; Darrell, T.; Malik, J. Rich feature hierarchies for accurate object detection and semantic segmentation. In Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition, Columbus, OH, USA, 23–28 June 2014; pp. 580–587. [Google Scholar]
- Ren, S.; He, K.; Girshick, R.; Sun, J. Faster r-cnn: Towards real-time object detection with region proposal networks. Adv. Neural Inf. Processing Syst.
**2015**, 28, 91–99. [Google Scholar] [CrossRef][Green Version] - Huang, J.; Rathod, V.; Sun, C.; Zhu, M.; Korattikara, A.; Fathi, A.; Fischer, I.; Wojna, Z.; Song, Y.; Guadarrama, S. Speed/accuracy trade-offs for modern convolutional object detectors. In Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition, Honolulu, HI, USA, 21–26 July 2017; pp. 7310–7311. [Google Scholar]
- Tan, M.; Le, Q. Efficientnet: Rethinking model scaling for convolutional neural networks. In Proceedings of the 36th International Conference on Machine Learning, Long Beach, CA, USA, 9–15 June 2019; pp. 6105–6114. [Google Scholar]
- Goh, G.B.; Hodas, N.O.; Siegel, C.; Vishnu, A. Smiles2vec: An interpretable general-purpose deep neural network for predicting chemical properties. arXiv
**2017**, arXiv:1712.02034. [Google Scholar] - Cui, Q.; Lu, S.; Ni, B.; Zeng, X.; Tan, Y.; Chen, Y.D.; Zhao, H. Improved prediction of aqueous solubility of novel compounds by going deeper with deep learning. Front. Oncol.
**2020**, 10, 121. [Google Scholar] [CrossRef] [PubMed] - Rao, J.; Zheng, S.; Song, Y.; Chen, J.; Li, C.; Xie, J.; Yang, H.; Chen, H.; Yang, Y. MolRep: A deep representation learning library for molecular property prediction. bioRxiv
**2021**. [Google Scholar] [CrossRef] - Wieder, O.; Kohlbacher, S.; Kuenemann, M.; Garon, A.; Ducrot, P.; Seidel, T.; Langer, T. A compact review of molecular property prediction with graph neural networks. Drug Discov. Today Technol.
**2020**, 37, 1–12. [Google Scholar] [CrossRef] [PubMed] - Feinberg, E.N.; Sur, D.; Wu, Z.; Husic, B.E.; Mai, H.; Li, Y.; Sun, S.; Yang, J.; Ramsundar, B.; Pande, V.S. PotentialNet for molecular property prediction. ACS Cent. Sci.
**2018**, 4, 1520–1530. [Google Scholar] [CrossRef] [PubMed] - Weininger, D. SMILES, a chemical language and information system. 1. Introduction to methodology and encoding rules. J. Chem. Inf. Comput. Sci.
**1988**, 28, 31–36. [Google Scholar] [CrossRef] - Gilmer, J.; Schoenholz, S.S.; Riley, P.F.; Vinyals, O.; Dahl, G.E. Neural message passing for quantum chemistry. In Proceedings of the International Conference on Machine Learning, Sydney, Australia, 6–11 August 2017; pp. 1263–1272. [Google Scholar]
- Xiong, Z.; Wang, D.; Liu, X.; Zhong, F.; Wan, X.; Li, X.; Li, Z.; Luo, X.; Chen, K.; Jiang, H. Pushing the boundaries of molecular representation for drug discovery with the graph attention mechanism. J. Med. Chem.
**2019**, 63, 8749–8760. [Google Scholar] [CrossRef] - Zhou, J.; Cui, G.; Zhang, Z.; Yang, C.; Liu, Z.; Wang, L.; Li, C.; Sun, M. Graph neural networks: A review of methods and applications. arXiv
**2018**, arXiv:1812.08434. [Google Scholar] [CrossRef] - Gomes, J.; Ramsundar, B.; Feinberg, E.N.; Pande, V.S. Atomic convolutional networks for predicting protein-ligand binding affinity. arXiv
**2017**, arXiv:1703.10603. [Google Scholar] - Coley, C.W.; Jin, W.; Rogers, L.; Jamison, T.F.; Jaakkola, T.S.; Green, W.H.; Barzilay, R.; Jensen, K.F. A graph-convolutional neural network model for the prediction of chemical reactivity. Chem. Sci.
**2019**, 10, 370–377. [Google Scholar] [CrossRef][Green Version] - Schütt, K.T.; Kindermans, P.-J.; Sauceda, H.E.; Chmiela, S.; Tkatchenko, A.; Müller, K.-R. Schnet: A continuous-filter convolutional neural network for modeling quantum interactions. arXiv
**2017**, arXiv:1706.08566. [Google Scholar] - Wu, Z.; Pan, S.; Chen, F.; Long, G.; Zhang, C.; Philip, S.Y. A comprehensive survey on graph neural networks. IEEE Trans. Neural Netw. Learn. Syst.
**2020**, 32, 4–24. [Google Scholar] [CrossRef] [PubMed][Green Version] - Segler, M.H.; Kogej, T.; Tyrchan, C.; Waller, M.P. Generating focused molecule libraries for drug discovery with recurrent neural networks. ACS Cent. Sci.
**2018**, 4, 120–131. [Google Scholar] [CrossRef] [PubMed][Green Version] - Kwon, S.; Yoon, S. Deepcci: End-to-end deep learning for chemical-chemical interaction prediction. In Proceedings of the 8th ACM International Conference on Bioinformatics, Computational Biology, and Health Informatics, Boston, MA, USA, 20–23 August 2017; pp. 203–212. [Google Scholar]
- Feng, Q.; Dueva, E.; Cherkasov, A.; Ester, M. Padme: A deep learning-based framework for drug-target interaction prediction. arXiv
**2018**, arXiv:1807.09741. [Google Scholar] - Schwaller, P.; Laino, T.; Gaudin, T.; Bolgar, P.; Hunter, C.A.; Bekas, C.; Lee, A.A. Molecular transformer: A model for uncertainty-calibrated chemical reaction prediction. ACS Cent. Sci.
**2019**, 5, 1572–1583. [Google Scholar] [CrossRef][Green Version] - Jo, J.; Kwak, B.; Choi, H.-S.; Yoon, S. The message passing neural networks for chemical property prediction on SMILES. Methods
**2020**, 179, 65–72. [Google Scholar] [CrossRef] [PubMed] - Graves, A.; Schmidhuber, J. Framewise phoneme classification with bidirectional LSTM and other neural network architectures. Neural Netw.
**2005**, 18, 602–610. [Google Scholar] [CrossRef] [PubMed] - Bjerrum, E.J. SMILES enumeration as data augmentation for neural network modeling of molecules. arXiv
**2017**, arXiv:1703.07076. [Google Scholar] - Nirmalakhandan, N.N.; Speece, R.E. Prediction of aqueous solubility of organic chemicals based on molecular structure. Environ. Sci. Technol.
**1988**, 22, 328–338. [Google Scholar] [CrossRef] - Bodor, N.; Harget, A.; Huang, M.J. Neural network studies. 1. Estimation of the aqueous solubility of organic compounds. J. Am. Chem. Soc.
**1991**, 113, 9480–9483. [Google Scholar] [CrossRef] - Huuskonen, J. Estimation of aqueous solubility for a diverse set of organic compounds based on molecular topology. J. Chem. Inf. Comput. Sci.
**2000**, 40, 773–777. [Google Scholar] [CrossRef] - Llinas, A.; Glen, R.C.; Goodman, J.M. Solubility challenge: Can you predict solubilities of 32 molecules using a database of 100 reliable measurements? J. Chem. Inf. Modeling
**2008**, 48, 1289–1303. [Google Scholar] [CrossRef] [PubMed] - Gupta, J.; Nunes, C.; Vyas, S.; Jonnalagadda, S. Prediction of solubility parameters and miscibility of pharmaceutical compounds by molecular dynamics simulations. J. Phys. Chem. B
**2011**, 115, 2014–2023. [Google Scholar] [CrossRef] [PubMed] - Lusci, A.; Pollastri, G.; Baldi, P. Deep architectures and deep learning in chemoinformatics: The prediction of aqueous solubility for drug-like molecules. J. Chem. Inf. Modeling
**2013**, 53, 1563–1575. [Google Scholar] [CrossRef] [PubMed][Green Version] - Li, L.; Totton, T.; Frenkel, D. Computational methodology for solubility prediction: Application to the sparingly soluble solutes. J. Chem. Phys.
**2017**, 146, 214110. [Google Scholar] [CrossRef][Green Version] - Tang, B.; Kramer, S.T.; Fang, M.; Qiu, Y.; Wu, Z.; Xu, D. A self-attention based message passing neural network for predicting molecular lipophilicity and aqueous solubility. J. Cheminform.
**2020**, 12, 15. [Google Scholar] [CrossRef] [PubMed][Green Version] - Panapitiya, G.; Girard, M.; Hollas, A.; Murugesan, V.; Wang, W.; Saldanha, E. Predicting aqueous solubility of organic molecules using deep learning models with varied molecular representations. arXiv
**2021**, arXiv:2105.12638. [Google Scholar] - Kipf, T.N.; Welling, M. Semi-supervised classification with graph convolutional networks. arXiv
**2016**, arXiv:1609.02907. [Google Scholar] - Li, M.; Zhou, J.; Hu, J.; Fan, W.; Zhang, Y.; Gu, Y.; Karypis, G. DGL-LifeSci: An open-source toolkit for deep learning on graphs in life science. arXiv
**2021**, arXiv:2106.14232. [Google Scholar] [CrossRef] - Wang, J.B.; Cao, D.S.; Zhu, M.F.; Yun, Y.H.; Xiao, N.; Liang, Y.Z. In silico evaluation of logD7. 4 and comparison with other prediction methods. J. Chemom.
**2015**, 29, 389–398. [Google Scholar] [CrossRef] - Zhang, D.; Xu, H.; Su, Z.; Xu, Y. Chinese comments sentiment classification based on word2vec and SVMperf. Expert Syst. Appl.
**2015**, 42, 1857–1863. [Google Scholar] [CrossRef] - Goldberg, Y.; Levy, O. word2vec Explained: Deriving mikolov et al.’s negative-sampling word-embedding method. arXiv
**2014**, arXiv:1402.3722. [Google Scholar] - Hochreiter, S.; Schmidhuber, J. Long short-term memory. Neural Comput.
**1997**, 9, 1735–1780. [Google Scholar] [CrossRef] - Woo, S.; Park, J.; Lee, J.-Y.; Kweon, I.S. Cbam: Convolutional block attention module. In Proceedings of the European Conference on Computer Vision (ECCV), Munich, Germany, 8–14 September 2018; pp. 3–19. [Google Scholar]
- Nair, V.; Hinton, G.E. Rectified linear units improve restricted boltzmann machines. In Proceedings of the ICML, Haifa, Israel, 21–24 June 2010. [Google Scholar]
- Snoek, J.; Larochelle, H.; Adams, R.P. Practical bayesian optimization of machine learning algorithms. Adv. Neural Inf. Processing Syst.
**2012**, 25, 2951–2959. [Google Scholar] - Bergstra, J.; Bardenet, R.; Bengio, Y.; Kégl, B. Algorithms for hyper-parameter optimization. Adv. Neural Inf. Processing Syst.
**2011**, 24, 2546–2554. [Google Scholar]

**Figure 1.**${R}^{2}$ curves of the BILSTM model (blue line) and BCSA model (red line) in (

**A**) the validation set, and (

**B**) of the test set.

**Figure 2.**Scatter plots of the predicted log solubilities of four different model. (

**A**) BCSA model with SMILES enumeration, (

**B**) GCN model on source canonical SMILES, (

**C**) AttentiveFP model on source canonical SMILES, and (

**D**) MPNN model on source canonical SMILES. The diagonal line in each plot denotes a perfect correlation (y = x).

**Figure 4.**The architecture of the BCSA model. We compress the smiles into vectors via data preprocessing to feed into our trained model. The model consists of three main components: a BILSTM, an improved Convolution Block Attention Module (CBAM) and a predicted MLP network with two fully connected dense layers. The CBAM model contains two parts: channel attention and spatial attention. Both attentions are used in parallel, then add to the outputs which are normalized with sigmoid function to obtain an information-enriched attention map.

Parameter | Possible Values | The Best Found |
---|---|---|

batch_size | (512,1024) | 1024 |

vocab_size | (120,150) | 120 |

Smiles_max_len | (150,200) | 150 |

hidden_size | (16,32,64) | 64 |

number_layers | 3–5 | 3 |

dropout | 0–0.6 | 0.12215 |

mlp_hidden_size | (32,64) | 32 |

learning_rate | 0.01–0.001 | 0.00966 |

Dataset | (Higher is Better) | (Lower is Better) | |||
---|---|---|---|---|---|

R^{2} | Spearman | RMSE | MAE | ||

Source data | validation | 0.8714 | 0.9294 | 0.8085 | 0.5671 |

Test | 0.8365 | 0.9185 | 0.9513 | 0.6435 | |

SMILES × 20 | validation | 0.8790 | 0.9352 | 0.8233 | 0.5512 |

Test | 0.8779 | 0.9339 | 0.8181 | 0.5493 | |

SMILES × 40 | validation | 0.8828 | 0.9375 | 0.8025 | 0.5207 |

Test | 0.8813 | 0.9361 | 0.7997 | 0.5226 |

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |

© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

## Share and Cite

**MDPI and ACS Style**

Hou, Y.; Wang, S.; Bai, B.; Chan, H.C.S.; Yuan, S.
Accurate Physical Property Predictions via Deep Learning. *Molecules* **2022**, *27*, 1668.
https://doi.org/10.3390/molecules27051668

**AMA Style**

Hou Y, Wang S, Bai B, Chan HCS, Yuan S.
Accurate Physical Property Predictions via Deep Learning. *Molecules*. 2022; 27(5):1668.
https://doi.org/10.3390/molecules27051668

**Chicago/Turabian Style**

Hou, Yuanyuan, Shiyu Wang, Bing Bai, H. C. Stephen Chan, and Shuguang Yuan.
2022. "Accurate Physical Property Predictions via Deep Learning" *Molecules* 27, no. 5: 1668.
https://doi.org/10.3390/molecules27051668