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Abstract Quantitative structure-activity relationship (QSAR) modeling is a powerful tool for drug discovery, yet the lack of interpretability of commonly used QSAR models hinders their application in molecular design. We propose a similarity-based regression framework, topological regression (TR), that offers a statistically grounded, computationally fast, and interpretable technique to predict drug responses. We compare the predictive performance of TR on 530 ChEMBL human target activity datasets against the predictive performance of deep-learning-based QSAR models. Our results suggest that our sparse TR model can achieve equal, if not better, performance than the deep learning-based QSAR models and provide better intuitive interpretation by extracting an approximate isometry between the chemical space of the drugs and their activity space.
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Interpretable Chirality-Aware Graph Neural Network for Quantitative Structure Activity Relationship Modeling in Drug Discovery
In computer-aided drug discovery, quantitative structure activity relation models are trained to predict biological activity from chemical structure. Despite the recent success of applying graph neural network to this task, important chemical information such as molecular chirality is ignored. To fill this crucial gap, we propose Molecular-Kernel Graph NeuralNetwork (MolKGNN) for molecular representation learning, which features SE(3)-/conformation invariance, chirality-awareness, and interpretability. For our MolKGNN, we first design a molecular graph convolution to capture the chemical pattern by comparing the atom's similarity with the learnable molecular kernels. Furthermore, we propagate the similarity score to capture the higher-order chemical pattern. To assess the method, we conduct a comprehensive evaluation with nine well-curated datasets spanning numerous important drug targets that feature realistic high class imbalance and it demonstrates the superiority of MolKGNN over other graph neural networks in computer-aided drug discovery. Meanwhile, the learned kernels identify patterns that agree with domain knowledge, confirming the pragmatic interpretability of this approach. Our code and supplementary material are publicly available at https://github.com/meilerlab/MolKGNN.
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- Award ID(s):
- 1763966
- PAR ID:
- 10486059
- Publisher / Repository:
- PKP Publishing Services Network
- Date Published:
- Journal Name:
- Proceedings of the AAAI Conference on Artificial Intelligence
- Volume:
- 37
- Issue:
- 12
- ISSN:
- 2159-5399
- Page Range / eLocation ID:
- 14356 to 14364
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1609/aaai.v37i12.26679
