Accelerating drug target inhibitor discovery with a deep generative foundation model.

Inhibitor discovery for emerging drug-target proteins is challenging, especially when target structure or active molecules are unknown. Here, we experimentally validate the broad utility of a deep generative framework trained at-scale on protein sequences, small molecules, and their mutual interactions-unbiased toward any specific target. We performed a protein sequence-conditioned sampling on the generative foundation model to design small-molecule inhibitors for two dissimilar targets: the spike protein receptor-binding domain (RBD) and the main protease from SARS-CoV-2.

Accelerated antimicrobial discovery via deep generative models and molecular dynamics simulations.

The de novo design of antimicrobial therapeutics involves the exploration of a vast chemical repertoire to find compounds with broad-spectrum potency and low toxicity. Here, we report an efficient computational method for the generation of antimicrobials with desired attributes. The method leverages guidance from classifiers trained on an informative latent space of molecules modelled using a deep generative autoencoder, and screens the generated molecules using deep-learning classifiers as well as physicochemical features derived from high-throughput molecular dynamics simulations.

Confronting data sparsity to identify potential sources of Zika virus spillover infection among primates.

The recent Zika virus (ZIKV) epidemic in the Americas ranks among the largest outbreaks in modern times. Like other mosquito-borne flaviviruses, ZIKV circulates in sylvatic cycles among primates that can serve as reservoirs of spillover infection to humans. Identifying sylvatic reservoirs is critical to mitigating spillover risk, but relevant surveillance and biological data remain limited for this and most other zoonoses.

Profiling antibodies to class II HLA in transplant patient sera.

Immunizing events including pregnancy, transfusions, and transplantation promote strong alloantibody responses to HLA. Such alloantibodies to HLA preclude organ transplantation, foster hyperacute rejection, and contribute to chronic transplant failure. Diagnostic antibody-screening assays detect alloreactive antibodies, yet key attributes including antibody concentration and isotype remain largely unexplored.