Title | ||
---|---|---|
CogMol: Target-Specific and Selective Drug Design for COVID-19 Using Deep Generative Models |
Abstract | ||
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The novel nature of SARS-CoV-2 calls for the development of efficient de novo
drug design approaches. In this study, we propose an end-to-end framework,
named CogMol (Controlled Generation of Molecules), for designing new drug-like
small molecules targeting novel viral proteins with high affinity and
off-target selectivity. CogMol combines adaptive pre-training of a molecular
SMILES Variational Autoencoder (VAE) and an efficient multi-attribute
controlled sampling scheme that uses guidance from attribute predictors trained
on latent features. To generate novel and optimal drug-like molecules for
unseen viral targets, CogMol leverages a protein-molecule binding affinity
predictor that is trained using SMILES VAE embeddings and protein sequence
embeddings learned unsupervised from a large corpus. CogMol framework is
applied to three SARS-CoV-2 target proteins: main protease, receptor-binding
domain of the spike protein, and non-structural protein 9 replicase. The
generated candidates are novel at both molecular and chemical scaffold levels
when compared to the training data. CogMol also includes insilico screening for
assessing toxicity of parent molecules and their metabolites with a multi-task
toxicity classifier, synthetic feasibility with a chemical retrosynthesis
predictor, and target structure binding with docking simulations. Docking
reveals favorable binding of generated molecules to the target protein
structure, where 87-95 % of high affinity molecules showed docking free energy
< -6 kcal/mol. When compared to approved drugs, the majority of designed
compounds show low parent molecule and metabolite toxicity and high synthetic
feasibility. In summary, CogMol handles multi-constraint design of
synthesizable, low-toxic, drug-like molecules with high target specificity and
selectivity, and does not need target-dependent fine-tuning of the framework or
target structure information. |
Year | Venue | DocType |
---|---|---|
2020 | NIPS 2020 | Conference |
Citations | PageRank | References |
0 | 0.34 | 0 |
Authors | ||
11 |
Name | Order | Citations | PageRank |
---|---|---|---|
V. Chenthamarakshan | 1 | 114 | 12.11 |
Payel Das | 2 | 43 | 12.59 |
Samuel C. Hoffman | 3 | 0 | 0.68 |
Hendrik Strobelt | 4 | 387 | 21.65 |
Inkit Padhi | 5 | 46 | 6.29 |
Kar Wai Lim | 6 | 61 | 4.79 |
Benjamin Hoover | 7 | 0 | 1.01 |
Matteo Manica | 8 | 7 | 7.61 |
Jannis Born | 9 | 6 | 3.88 |
T. Laino | 10 | 6 | 3.98 |
Aleksandra Mojsilovic | 11 | 288 | 39.15 |