# Can Pre-trained Models Really Learn Better Molecular Representations for AI-aided Drug Discovery?

arXiv: https://arxiv.org/abs/2209.07423 · HTML: https://mlsanity.com/paper/2209.07423/

## Key facts

- Cited by 2 papers in the map (data through 14 Oct 2026).
- Builds on 15 of its 35 references that are in the map.
- First posted on arXiv 21 Aug 2022.

## Builds on (most cited first, 15 of 15)

- [FaceNet: A Unified Embedding for Face Recognition and Clustering](https://mlsanity.com/paper/1503.03832/) (2015)
- [MoleculeNet: A Benchmark for Molecular Machine Learning](https://mlsanity.com/paper/1703.00564/) (2017)
- [Strategies for Pre-training Graph Neural Networks](https://mlsanity.com/paper/1905.12265/) (2019)
- [OGB-LSC: A Large-Scale Challenge for Machine Learning on Graphs](https://mlsanity.com/paper/2103.09430/) (2021)
- [Do Transformers Really Perform Bad for Graph Representation?](https://mlsanity.com/paper/2106.05234/) (2021)
- [LEEP: A New Measure to Evaluate Transferability of Learned Representations](https://mlsanity.com/paper/2002.12462/) (2020)
- [LogME: Practical Assessment of Pre-trained Models for Transfer Learning](https://mlsanity.com/paper/2102.11005/) (2021)
- [Motif-based Graph Self-Supervised Learning for Molecular Property Prediction](https://mlsanity.com/paper/2110.00987/) (2021)
- [Transferability and Hardness of Supervised Classification Tasks](https://mlsanity.com/paper/1908.08142/) (2019)
- [Self-supervised Graph-level Representation Learning with Local and Global Structure](https://mlsanity.com/paper/2106.04113/) (2021)
- [Molecule Attention Transformer](https://mlsanity.com/paper/2002.08264/) (2020)
- [SMILES Transformer: Pre-trained Molecular Fingerprint for Low Data Drug Discovery](https://mlsanity.com/paper/1911.04738/) (2019)
- [DrugOOD: Out-of-Distribution (OOD) Dataset Curator and Benchmark for AI-aided Drug Discovery -- A Focus on Affinity Prediction Problems with Noise Annotations](https://mlsanity.com/paper/2201.09637/) (2022)
- [Frustratingly Easy Transferability Estimation](https://mlsanity.com/paper/2106.09362/) (2021)
- [Exploiting Neuron and Synapse Filter Dynamics in Spatial Temporal Learning of Deep Spiking Neural Network](https://mlsanity.com/paper/2003.02944/) (2020)

## Built on by (most cited first, 2 of 2)

- [Bidirectional Generation of Structure and Properties Through a Single Molecular Foundation Model](https://mlsanity.com/paper/2211.10590/) (2022)
- [Contextual Molecule Representation Learning from Chemical Reaction Knowledge](https://mlsanity.com/paper/2402.13779/) (2024)

## Abstract (arXiv)

Self-supervised pre-training is gaining increasingly more popularity in AI-aided drug discovery, leading to more and more pre-trained models with the promise that they can extract better feature representations for molecules. Yet, the quality of learned representations have not been fully explored. In this work, inspired by the two phenomena of Activity Cliffs (ACs) and Scaffold Hopping (SH) in traditional Quantitative Structure-Activity Relationship (QSAR) analysis, we propose a method named Representation-Property Relationship Analysis (RePRA) to evaluate the quality of the representations extracted by the pre-trained model and visualize the relationship between the representations and properties. The concepts of ACs and SH are generalized from the structure-activity context to the representation-property context, and the underlying principles of RePRA are analyzed theoretically. Two scores are designed to measure the generalized ACs and SH detected by RePRA, and therefore the quality of representations can be evaluated. In experiments, representations of molecules from 10 target tasks generated by 7 pre-trained models are analyzed. The results indicate that the state-of-the-art pre-trained models can overcome some shortcomings of canonical Extended-Connectivity FingerPrints (ECFP), while the correlation between the basis of the representation space and specific molecular substructures are not explicit. Thus, some representations could be even worse than the canonical fingerprints. Our method enables researchers to evaluate the quality of molecular representations generated by their proposed self-supervised pre-trained models. And our findings can guide the community to develop better pre-training techniques to regularize the occurrence of ACs and SH.