Finally, to overcome the limitations of molecular designs that depend on training data, as shown in this study, the use of methods that do not rely on currently available data is essential. As specific strategies, adding new data or predicting properties through molecular simulations based on physicochemical backgrounds can be considered. Although adding new data is costly, it is expected to expand the AD, thereby enabling reliable molecular design in a broader chemical space. Incorporating the estimation of physical properties by quantum chemistry, all-atom, coarse-grained, or docking simulations into molecular design is also a promising strategy. Indeed, experimental validation of functional molecules designed by quantum chemistry calculations has been reported . While it is challenging to simulate all properties, including permeability and pharmacokinetics, as addressed in this study, utilizing the available simulation techniques to verify and design molecules with low reliability will be necessary in the future.