Andrei Cristian Nica

Generative Active Learning for the Search of Small-molecule Protein Binders

Maksym Korablyov

Cheng-Hao Liu

Moksh J. Jain

Almer M. van der Sloot

Eric Jolicoeur

Edward Ruediger

Andrei Cristian Nica

Emmanuel Bengio

Kostiantyn Lapchevskyi

Daniel St-Cyr

Doris Alexandra Schuetz

Victor I Butoi

Jarrid Rector-Brooks

Simon R. Blackburn

Leo Feng

Hadi Nekoei

Sai Krishna Gottipati

Priyesh Vijayan

Prateek Gupta

Ladislav Rampasek … (see 14 more)

Sasikanth Avancha

Pierre-Luc Bacon

William L. Hamilton

Brooks Paige

Sanchit Misra

Stanisław Jastrzębski

Bharat Kaul

Doina Precup

José Miguel Hernández-Lobato

Marwin Segler

Michael M. Bronstein

Anne Marinier

Mike Tyers

Yoshua Bengio

Despite substantial progress in machine learning for scientific discovery in recent years, truly de novo design of small molecules which exh… (see more)ibit a property of interest remains a significant challenge. We introduce LambdaZero, a generative active learning approach to search for synthesizable molecules. Powered by deep reinforcement learning, LambdaZero learns to search over the vast space of molecules to discover candidates with a desired property. We apply LambdaZero with molecular docking to design novel small molecules that inhibit the enzyme soluble Epoxide Hydrolase 2 (sEH), while enforcing constraints on synthesizability and drug-likeliness. LambdaZero provides an exponential speedup in terms of the number of calls to the expensive molecular docking oracle, and LambdaZero de novo designed molecules reach docking scores that would otherwise require the virtual screening of a hundred billion molecules. Importantly, LambdaZero discovers novel scaffolds of synthesizable, drug-like inhibitors for sEH. In in vitro experimental validation, a series of ligands from a generated quinazoline-based scaffold were synthesized, and the lead inhibitor N-(4,6-di(pyrrolidin-1-yl)quinazolin-2-yl)-N-methylbenzamide (UM0152893) displayed sub-micromolar enzyme inhibition of sEH.

2024-05-02

ArXiv (preprint)

doi.org

arxiv.org

Learning GFlowNets from partial episodes for improved convergence and stability

Moksh J. Jain

Tom Bosc

Generative flow networks (GFlowNets) are a family of algorithms for training a sequential sampler of discrete objects under an unnormalized … (see more)target density and have been successfully used for various probabilistic modeling tasks. Existing training objectives for GFlowNets are either local to states or transitions, or propagate a reward signal over an entire sampling trajectory. We argue that these alternatives represent opposite ends of a gradient bias-variance tradeoff and propose a way to exploit this tradeoff to mitigate its harmful effects. Inspired by the TD(

2023-01-01

ICML (published)

doi.org

openreview.net

The Paradox of Choice: On the Role of Attention in Hierarchical Reinforcement Learning

Andrei Cristian Nica

Khimya Khetarpal

Doina Precup

Decision-making AI agents are often faced with two important challenges: the depth of the planning horizon, and the branching factor due to … (see more)having many choices. Hierarchical reinforcement learning methods aim to solve the first problem, by providing shortcuts that skip over multiple time steps. To cope with the breadth, it is desirable to restrict the agent's attention at each step to a reasonable number of possible choices. The concept of affordances (Gibson, 1977) suggests that only certain actions are feasible in certain states. In this work, we first characterize "affordances" as a "hard" attention mechanism that strictly limits the available choices of temporally extended options. We then investigate the role of hard versus soft attention in training data collection, abstract value learning in long-horizon tasks, and handling a growing number of choices. To this end, we present an online, model-free algorithm to learn affordances that can be used to further learn subgoal options. Finally, we identify and empirically demonstrate the settings in which the "paradox of choice" arises, i.e. when having fewer but more meaningful choices improves the learning speed and performance of a reinforcement learning agent.

2022-10-20

NeurIPS.cc/2022/Workshop/Attention (poster)

openreview.net

E VALUATING G ENERALIZATION IN GF LOW N ETS FOR M OLECULE D ESIGN

Moksh J. Jain

Cheng-Hao Liu

Michael M. Bronstein

Deep learning bears promise for drug discovery problems such as de novo molecular design. Generating data to train such models is a costly a… (see more)nd time-consuming process, given the need for wet-lab experiments or expensive simulations. This problem is compounded by the notorious data-hungriness of machine learning algorithms. In small molecule generation the recently proposed GFlowNet method has shown good performance in generating diverse high-scoring candidates, and has the interesting advantage of being an off-policy offline method. Finding an appropriate generalization evaluation metric for such models, one predictive of the desired search performance (i.e. finding high-scoring diverse candidates), will help guide online data collection for such an algorithm. In this work, we develop techniques for evaluating GFlowNet performance on a test set, and identify the most promising metric for predicting generalization. We present empirical results on several small-molecule design tasks in drug discovery, for several GFlowNet training setups, and we find a metric strongly correlated with diverse high-scoring batch generation. This metric should be used to identify the best generative model from which to sample batches of molecules to be evaluated.

2022-04-05

ICLR.cc/2022/Workshop/MLDD (poster)

openreview.net