Transformers are machine learning models originally developed to translate between natural languages. Recently, a transformer model was trained on knowledge of medicinal chemistry, i.e., matched molecular pairs of nearly a million bioactive compounds from the ChEMBL database. Here, we customize (i.e., fine-tune) the pretrained model to enhance the affinity and/or metabolic stability of a series of inhibitors of methyltransferase-like protein 3 (METTL3). We first fine-tune the transformer model using a data set of about 500 METTL3 inhibitors with known binding affinities and validate it by retrospective analysis. Then, we fine-tune the original transformer model to simultaneously optimize binding affinity and metabolic stability in a prospective application. Two of the five METTL3 inhibitors predicted by the multiobjective optimized model show low-nanomolar potency and higher stability than the lead compound of the chemical series used for fine-tuning.
BT - ACS Bio & Med Chem Au C1 - 0315 DA - 2026 Jan 20 DO - 10.1021/acsbiomedchemau.5c00198 IS - 2 J2 - ACS Bio Med Chem Au LA - eng M3 - Research Article N2 -Transformers are machine learning models originally developed to translate between natural languages. Recently, a transformer model was trained on knowledge of medicinal chemistry, i.e., matched molecular pairs of nearly a million bioactive compounds from the ChEMBL database. Here, we customize (i.e., fine-tune) the pretrained model to enhance the affinity and/or metabolic stability of a series of inhibitors of methyltransferase-like protein 3 (METTL3). We first fine-tune the transformer model using a data set of about 500 METTL3 inhibitors with known binding affinities and validate it by retrospective analysis. Then, we fine-tune the original transformer model to simultaneously optimize binding affinity and metabolic stability in a prospective application. Two of the five METTL3 inhibitors predicted by the multiobjective optimized model show low-nanomolar potency and higher stability than the lead compound of the chemical series used for fine-tuning.
PY - 2026 SP - 160 EP - 167 T2 - ACS Bio & Med Chem Au TI - Fine-Tuning a Transformer Model for METTL3 Lead Optimization UR - https://pubs.acs.org/doi/10.1021/acsbiomedchemau.5c00198 VL - 6 ER -