Perplexity-based molecule ranking and bias estimation of chemical language models

Chemical language models (CLMs) can be employed to design molecules with desired properties. CLMs generate new chemical structures in the form of textual representations, such as the simplified molecular input line entry systems (SMILES) strings, in a rule-free manner. However, the quality of these de novo generated molecules is difficult to assess a priori. In this study, we apply the perplexity metric to determine the degree to which the molecules generated by a CLM match the desired design objectives. This model-intrinsic score allows identifying and ranking the most promising molecular designs based on the probabilities learned by the CLM. Using perplexity to compare “greedy” (beam search) with “explorative” (multinomial sampling) methods for SMILES generation, certain advantages of multinomial sampling become apparent. Additionally, perplexity scoring is performed to identify undesired model biases introduced during model training and allows the development of a new ranking system to remove those undesired biases.