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Efficient multi-objective molecular optimization in a continuous latent space.

ABSTRACT: One of the main challenges in small molecule drug discovery is finding novel chemical compounds with desirable properties. In this work, we propose a novel method that combines in silico prediction of molecular properties such as biological activity or pharmacokinetics with an in silico optimization algorithm, namely Particle Swarm Optimization. Our method takes a starting compound as input and proposes new molecules with more desirable (predicted) properties. It navigates a machine-learned continuous representation of a drug-like chemical space guided by a defined objective function. The objective function combines multiple in silico prediction models, defined desirability ranges and substructure constraints. We demonstrate that our proposed method is able to consistently find more desirable molecules for the studied tasks in relatively short time. We hope that our method can support medicinal chemists in accelerating and improving the lead optimization process.

SUBMITTER: Winter R

PROVIDER: S-EPMC6836962 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Efficient multi-objective molecular optimization in a continuous latent space.

Winter Robin R Montanari Floriane F Steffen Andreas A Briem Hans H Noé Frank F Clevert Djork-Arné DA

Chemical science 20190708 34

One of the main challenges in small molecule drug discovery is finding novel chemical compounds with desirable properties. In this work, we propose a novel method that combines <i>in silico</i> prediction of molecular properties such as biological activity or pharmacokinetics with an <i>in silico</i> optimization algorithm, namely Particle Swarm Optimization. Our method takes a starting compound as input and proposes new molecules with more desirable (predicted) properties. It navigates a machin ...[more]

PMID: 31853357

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Project description:In scientific disciplines, benchmarks play a vital role in driving progress forward. For a benchmark to be effective, it must closely resemble real-world tasks. If the level of difficulty or relevance is inadequate, it can impede progress in the field. Moreover, benchmarks should have low computational overhead to ensure accessibility and repeatability. The objective is to achieve a kind of ``Turing test'' by creating a surrogate model that is practically indistinguishable from the ground truth observation, at least within the dataset's explored boundaries. This objective necessitates a large quantity of data. This data encompasses numerous features that are characteristic of chemistry and materials science optimization tasks that are relevant to industry. These features include high levels of noise, multiple fidelities, multiple objectives, linear constraints, non-linear correlations, and failure regions. We performed 494498 random hard-sphere packing simulations representing 206 CPU days' worth of computational overhead. Simulations required nine input parameters with linear constraints and two discrete fidelities each with continuous fidelity parameters. The data was logged in a free-tier shared MongoDB Atlas database, producing two core tabular datasets: a failure probability dataset and a regression dataset. The failure probability dataset maps unique input parameter sets to the estimated probabilities that the simulation will fail. The regression dataset maps input parameter sets (including repeats) to particle packing fractions and computational runtimes for each of the two steps. These two datasets were used to create a surrogate model as close as possible to running the actual simulations by incorporating simulation failure and heteroskedastic noise. In the regression dataset, percentile ranks were calculated for each group of identical parameter sets to account for heteroskedastic noise, thereby ensuring reliable and accurate data. This differs from the conventional approach that imposes a-priori assumptions, such as Gaussian noise, by specifying mean and standard deviation. This technique can be extended to other benchmark datasets to bridge the gap between optimization benchmarks with low computational overhead and the complex optimization scenarios encountered in the real world.

Dataset Information

Efficient multi-objective molecular optimization in a continuous latent space.

Publications

Efficient multi-objective molecular optimization in a continuous latent space.

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