Ben Fauber

Rahul Nandakumar, Ben Fauber, Deepayan Chakrabarti

Drug discovery seeks molecules (ligands) that bind strongly and selectively to a target protein. However, fewer than 5% of candidate ligands pass the bar for even the early stages of drug discovery. Furthermore, we want methods that work for novel proteins for which we have no prior data. Starting from scratch, we have to iteratively select and test candidate ligands such that we find enough ligands of the desired quality in as few tests as possible. Our proposed algorithm, named SPADE, introduces a novel approach to ligand selection that requires only 40 tests on average to find 10 high-quality ligands. In one-vs-one comparisons, SPADE outperforms deep learning and Bayesian optimization methods on more proteins, achieving median improvements of 7%-32% in sample efficiency. SPADE is also 10x faster than its closest competitor at scoring candidate drugs. Dataset and code is available at https://anonymous.4open.science/r/SPADE_Fast_Drug_Discovery_by_Learning_from_Sparse_Data-F028/README.md

Ben Fauber

We propose that small pretrained foundational generative language models with millions of parameters can be utilized as a general learning framework for sequence-based tasks. Our proposal overcomes the computational resource, skill set, and timeline challenges associated with training neural networks and language models from scratch. Further, our approach focuses on creating small and highly specialized models that can accurately execute a challenging task of which the base model is incapable of performing. We demonstrate that 125M, 350M, and 1.3B parameter pretrained foundational language models can be instruction fine-tuned with 10,000-to-1,000,000 instruction examples to achieve near state-of-the-art results on challenging cheminformatics tasks. We also demonstrate the role of successive language model fine-tuning epochs on improved outcomes, as well as the importance of both data formatting and pretrained foundational language model selection for instruction fine-tuning success.

Ben Fauber

We demonstrate that Gini coefficients can be used as unified metrics to evaluate many-versus-many (all-to-all) similarity in vector spaces. Our analysis of various image datasets shows that images with the highest Gini coefficients tend to be the most similar to one another, while images with the lowest Gini coefficients are the least similar. We also show that this relationship holds true for vectorized text embeddings from various corpuses, highlighting the consistency of our method and its broad applicability across different types of data. Additionally, we demonstrate that selecting machine learning training samples that closely match the distribution of the testing dataset is far more important than ensuring data diversity. Selection of exemplary and iconic training samples with higher Gini coefficients leads to significantly better model performance compared to simply having a diverse training set with lower Gini coefficients. Thus, Gini coefficients can serve as effective criteria for selecting machine learning training samples, with our selection method outperforming random sampling methods in very sparse information settings.

Ben Fauber

We describe the accurate prediction of ligand-protein interaction (LPI) affinities, also known as drug-target interactions (DTI), with instruction fine-tuned pretrained generative small language models (SLMs). We achieved accurate predictions for a range of affinity values associated with ligand-protein interactions on out-of-sample data in a zero-shot setting. Only the SMILES string of the ligand and the amino acid sequence of the protein were used as the model inputs. Our results demonstrate a clear improvement over machine learning (ML) and free-energy perturbation (FEP+) based methods in accurately predicting a range of ligand-protein interaction affinities, which can be leveraged to further accelerate drug discovery campaigns against challenging therapeutic targets.