Yucui Xin, Yingsheng Zhang DOI: https://doi.org/10.3389/fonc.2023.1168143 Abstract: Tumor cells can result from gene mutations and over-expression. Synthetic lethality (SL) offers a desirable setting where cancer cells bearing one mutated gene of an SL gene pair can be specifically targeted by disrupting the function of the other genes, while leaving wide-type normal cells unharmed. Paralogs, a set of homologous genes that have diverged from each other as a consequence of gene duplication, make the concept of SL feasible as the loss of one gene does not affect the cell’s survival. Furthermore, homozygous loss of paralogs in tumor cells is more frequent than singletons, making them ideal SL targets. Although high-throughput CRISPR-Cas9 screenings have uncovered numerous paralog-based SL pairs, the unclear mechanisms of targeting these gene pairs and the...

Weisheng Zheng, Mengchen Pu, Xiaorong Li, Zhaolan Du, Sutong Jin, Xingshuai Li, Jielong Zhou, Yingsheng Zhang DOI: https://doi.org/10.1038/s41598-023-35842-w Abstract: Metastatic propagation is the leading cause of death for most cancers. Prediction and elucidation of metastatic process is crucial for the treatment of cancer. Even though somatic mutations have been linked to tumorigenesis and metastasis, it is less explored whether metastatic events can be identified through genomic mutational signatures, which are concise descriptions of the mutational processes. Here, we developed MetaWise, a Deep Neural Network (DNN) model, by applying mutational signatures as input features calculated from Whole-Exome Sequencing (WES) data of TCGA and other metastatic cohorts. This model can accurately classify metastatic tumors from primary tumors and outpe...

Feng Zhou, Shiqiu Yin, Yi Xiao, Zaiyun Lin, Weiqiang Fu, and Yingsheng J. Zhang DOI: https://doi.org/10.1021/acsomega.3c02294 Abstract: Drug design based on kinetic properties is growing in application. Here, we applied retrosynthesis-based pre-trained molecular representation (RPM) in machine learning (ML) to train 501 inhibitors of 55 proteins and successfully predicted the dissociation rate constant (koff) values of 38 inhibitors from an independent dataset for the N-terminal domain of heat shock protein 90α (N-HSP90). Our RPM molecular representation outperforms other pre-trained molecular representations such as GEM, MPG, and general molecular descriptors from RDKit. Furthermore, we optimized the accelerated molecular dynamics to calculate the relative retention time (RT) for the 128 inhibitors of N-HSP90 and obtained the protei...

Zaiyun Lin, Shiqiu Yin, Lei Shi, Wenbiao Zhou, and Yingsheng John Zhang DOI: https://doi.org/10.1021/acs.jcim.2c01302 Abstract: Retrosynthesis prediction, the task of identifying reactant molecules that can be usedto synthesize product molecules, is a fundamental challenge in organic chemistry and related fields.To address this challenge, we propose a novel graph-to-graph transformation model, G2GT. Themodel is built on the standard transformer structure and utilizes graph encoders and decoders.Additionally, we demonstrate the effectiveness of self-training, a data augmentation technique thatutilizes unlabeled molecular data, in improving the performance of the model. To further enhancediversity, we propose a weak ensemble method, inspired by reaction-type labels and ensemblelearning. This method incorporates beam search, nucleus sampling, and top-k sampling to im...

Li, Y., Yuan, T., Huang, B. et al.  Nat Commun 14, 1030 (2023). https://doi.org/10.1038/s41467-023-36766-9 Abstract The sodium channel NaV1.6 is widely expressed in neurons of the central and peripheral nervous systems, which plays a critical role in regulating neuronal excitability. Dysfunction of NaV1.6 has been linked to epileptic encephalopathy, intellectual disability and movement disorders. Here we present cryo-EM structures of human NaV1.6/β1/β2 alone and complexed with a guanidinium neurotoxin 4,9-anhydro-tetrodotoxin (4,9-ah-TTX), revealing molecular mechanism of NaV1.6 inhibition by the blocker. The apo-form structure reveals two potential Na+ binding sites within the selectivity filter, suggesting a possible mechanism for Na+ selectivity and conductance. In the 4,9-ah-TTX bound structure, 4,9-ah-TTX bin...

Cell. October 04, 2022 DOI:https://doi.org/10.1016/j.cell.2022.09.037 Liming Yan, Yucen Huang,  Ji Ge, Zhenyu Liu, Pengchi Lu, Bo Huang, Shan Gao, Junbo Wang, Liping Tan, Sihan Ye, Fengxi Yu, Weiqi Lan, Shiya Xu, Feng Zhou, Lei Shi, Luke W. Guddat, Yan Gao, Zihe Rao, Zhiyong Lou Summary Decoration of cap on viral RNA plays essential roles in SARS-CoV-2 proliferation. Here we report a mechanism for SARS-CoV-2 RNA capping and document structural details at atomic resolution. The NiRAN domain in polymerase catalyzes the covalent link of RNA 5’ end to the first residue of nsp9 (termed as RNAylation), thus being an intermediate to form cap core (GpppA) with GTP catalyzed again by NiRAN. We also reveal that triphosphorylated nucleotide analogue inhibitors can be bonded to nsp9 and fi...