ALipSol: An Attention-Driven Mixture-of-Experts Model for Lipophilicity and Solubility Prediction.

ABSTRACT

Lipophilicity (logD) and aqueous solubility (logSw) play a central role in drug development. The accurate prediction of these properties remains to be solved due to data scarcity. Current methodologies neglect the intrinsic relationships between physicochemical properties and usually ignore the ionization effects. Here, we propose an attention-driven mixture-of-experts (MoE) model named ALipSol, which explicitly reproduces the hierarchy of task relationships. We adopt the principle of divide-and-conquer by breaking down the complex end point (logD or logSw) into simpler ones (acidic pKa, basic pKa, and logP) and allocating a specific expert network for each subproblem. Subsequently, we implement transfer learning to extract knowledge from related tasks, thus alleviating the dilemma of limited data. Additionally, we substitute the gating network with an attention mechanism to better capture the dynamic task relationships on a per-example basis. We adopt local fine-tuning and consensus prediction to further boost model performance. Extensive evaluation experiments verify the success of the ALipSol model, which achieves RMSE improvement of 8.04%, 2.49%, 8.57%, 12.8%, and 8.60% on the Lipop, ESOL, AqSolDB, external logD, and external logS data sets, respectively, compared with Attentive FP and the state-of-the-art in silico tools. In particular, our model yields more significant advantages (Welch's t-test) for small training data, implying its high robustness and generalizability. The interpretability analysis proves that the atom contributions learned by ALipSol are more reasonable compared with the vanilla Attentive FP, and the substitution effects in benzene derivatives agreed well with empirical constants, revealing the potential of our model to extract useful patterns from data and provide guidance for lead optimization.