Ultrafast Shape Recognition (USR), along with its derivatives, are Ligand-Based Virtual Screening (LBVS) methods that condense 3-dimensional information about molecular shape, as well as other properties, into a small set of numeric descriptors. These can be used to efficiently compute a measure of similarity between pairs of molecules using a simple inverse Manhattan Distance metric. In this study we explore the use of suitable Machine Learning techniques that can be trained using USR descriptors, so as to improve the similarity detection of potential new leads. We use molecules from the Directory for Useful Decoys-Enhanced to construct machine learning models based on three different algorithms: Gaussian Mixture Models (GMMs), Isolation Forests and Artificial Neural Networks (ANNs). We train models based on full molecule conformer models, as well as the Lowest Energy Conformations (LECs) only. We also investigate the performance of our models when trained on smaller datasets so as to model virtual screening scenarios when only a small number of actives are known a priori. Our results indicate significant performance gains over a state of the art USR-derived method, ElectroShape 5D, with GMMs obtaining a mean performance up to 430% better than that of ElectroShape 5D in terms of Enrichment Factor with a maximum improvement of up to 940%. Additionally, we demonstrate that our models are capable of maintaining their performance, in terms of enrichment factor, within 10% of the mean as the size of the training dataset is successively reduced. Furthermore, we also demonstrate that running times for retrospective screening using the machine learning models we selected are faster than standard USR, on average by a factor of 10, including the time required for training. Our results show that machine learning techniques can significantly improve the virtual screening performance and efficiency of the USR family of methods.