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Noise Contrastive Estimation (NCE) is a widely used method for training generative models, typically used as an alternative to Maximum Likelihood Estimation (MLE) when exact computations of probability are hard. NCE trains generative models by discriminating between data and appropriately chosen noise distributions. Although NCE is statistically consistent, it suffers from slow convergence and high variance when there is small overlap between the noise and data distributions. Both these problems are related to the flatness of the NCE loss landscape. We propose an innovative approach to circumvent slow convergence rates by quick inference of the optimal normalizing constant at every gradient step. This allows the rest of the parameters to have more freedom during NCE optimization. We analyze the use of both binary search and the Bennett Acceptance Ratio (BAR) for quick computation of the normalizing constant and show improved performance for both methods on convex and non-convex settings. 

The CACHE challenges are a series of prospective benchmarking exercises to evaluate progress in the field of computational hit-finding. Here we report the results of the inaugural CACHE challenge in which 23 computational teams each selected up to 100 commercially available compounds that they predicted would bind to the WDR domain of the Parkinson’s disease target LRRK2, a domain with no known ligand and only an apo structure in the PDB. The lack of known binding data and presumably low druggability of the target is a challenge to computational hit finding methods. Of the 1955 molecules predicted by participants in Round 1 of the challenge, 73 were found to bind to LRRK2 in an SPR assay with a KD lower than 150 μM. These 73 molecules were advanced to the Round 2 hit expansion phase, where computational teams each selected up to 50 analogs. Binding was observed in two orthogonal assays for seven chemically diverse series, with affinities ranging from 18 to 140 μM. The seven successful computational workflows varied in their screening strategies and techniques. Three used molecular dynamics to produce a conformational ensemble of the targeted site, three included a fragment docking step, three implemented a generative design strategy and five used one or more deep learning steps. CACHE #1 reflects a highly exploratory phase in computational drug design where participants adopted strikingly diverging screening strategies. Machine learning-accelerated methods achieved similar results to brute force (e.g., exhaustive) docking. First-in-class, experimentally confirmed compounds were rare and weakly potent, indicating that recent advances are not sufficient to effectively address challenging targets.