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  • Geometric Deep Learning for Structure-Based Ligand Design. ACS central science Powers, A. S., Yu, H. H., Suriana, P., Koodli, R. V., Lu, T., Paggi, J. M., Dror, R. O. 2023; 9 (12): 2257-2267

    Abstract

    A pervasive challenge in drug design is determining how to expand a ligand-a small molecule that binds to a target biomolecule-in order to improve various properties of the ligand. Adding single chemical groups, known as fragments, is important for lead optimization tasks, and adding multiple fragments is critical for fragment-based drug design. We have developed a comprehensive framework that uses machine learning and three-dimensional protein-ligand structures to address this challenge. Our method, FRAME, iteratively determines where on a ligand to add fragments, selects fragments to add, and predicts the geometry of the added fragments. On a comprehensive benchmark, FRAME consistently improves predicted affinity and selectivity relative to the initial ligand, while generating molecules with more drug-like chemical properties than docking-based methods currently in widespread use. FRAME learns to accurately describe molecular interactions despite being given no prior information on such interactions. The resulting framework for quality molecular hypothesis generation can be easily incorporated into the workflows of medicinal chemists for diverse tasks, including lead optimization, fragment-based drug discovery, and de novo drug design.

    View details for DOI 10.1021/acscentsci.3c00572

    View details for PubMedID 38161364

  • EternaBrain: Automated RNA design through move sets and strategies from an Internet-scale RNA videogame. PLoS computational biology Koodli, R. V., Keep, B. n., Coppess, K. R., Portela, F. n., Das, R. n. 2019; 15 (6): e1007059

    Abstract

    Emerging RNA-based approaches to disease detection and gene therapy require RNA sequences that fold into specific base-pairing patterns, but computational algorithms generally remain inadequate for these secondary structure design tasks. The Eterna project has crowdsourced RNA design to human video game players in the form of puzzles that reach extraordinary difficulty. Here, we demonstrate that Eterna participants' moves and strategies can be leveraged to improve automated computational RNA design. We present an eternamoves-large repository consisting of 1.8 million of player moves on 12 of the most-played Eterna puzzles as well as an eternamoves-select repository of 30,477 moves from the top 72 players on a select set of more advanced puzzles. On eternamoves-select, we present a multilayer convolutional neural network (CNN) EternaBrain that achieves test accuracies of 51% and 34% in base prediction and location prediction, respectively, suggesting that top players' moves are partially stereotyped. Pipelining this CNN's move predictions with single-action-playout (SAP) of six strategies compiled by human players solves 61 out of 100 independent puzzles in the Eterna100 benchmark. EternaBrain-SAP outperforms previously published RNA design algorithms and achieves similar or better performance than a newer generation of deep learning methods, while being largely orthogonal to these other methods. Our study provides useful lessons for future efforts to achieve human-competitive performance with automated RNA design algorithms.

    View details for DOI 10.1371/journal.pcbi.1007059

    View details for PubMedID 31247029