期刊：Nature Communications?volume?15, Article?number:?3985?(2024)

作者：Wanbiao Chen,?Rongfeng Zou,?Yi Mei,?Jiawei Li,?Yumi Xuan,?Bing Cui,?Junjie Zou,?Juncheng Wang,?Shaoquan Lin,?Zhe Zhang?&?Chongyuan Wang

時間：2024.05.11

Pentamidine and melarsoprol are primary drugs used to treat the lethal human sleeping sickness caused by the parasite?Trypanosoma brucei. Cross-resistance to these two drugs has recently been linked to aquaglyceroporin 2 of the trypanosome (TbAQP2). TbAQP2 is the first member of the aquaporin family described as capable of drug transport; however, the underlying mechanism remains unclear. Here, we present cryo-electron microscopy structures of TbAQP2 bound to pentamidine or melarsoprol. Our structural studies, together with the molecular dynamic simulations, reveal the mechanisms shaping substrate specificity and drug permeation. Multiple amino acids in TbAQP2, near the extracellular entrance and inside the pore, create an expanded conducting tunnel, sterically and energetically allowing the permeation of pentamidine and melarsoprol. Our study elucidates the mechanism of drug transport by TbAQP2, providing valuable insights to inform the design of drugs against trypanosomiasis.

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期刊：Methods Volume 222,?February 2024, Pages 112-121

作者：Lianjun?Zheng,?Fangjun?Shi,?Chunwang?Peng,?Min?Xu,?Fangda?Fan,?Yuanpeng?Li,?Lin?Zhang,?Jiewen?Du,?Zonghu?Wang,?Zhixiong?Lin,?Yina?Sun,?Chenglong?Deng,?Xinli?Duan,?Lin?Wei,?Chuanfang?Zhao,?Lei?Fang,?Peiyu?Zhang,?Songling?Ma,?Lipeng?Lai,?Mingjun?Yang?

時間：2024.01.11

Design of molecules for candidate compound selection is one of the central challenges in drug discovery due to the complexity of chemical space and requirement of multi-parameter optimization. Here we present an application scenario-oriented platform (ID4Idea) for molecule generation in different scenarios of drug discovery. This platform utilizes both library or rule based and generative based algorithms (VAE,?RNN, GAN, etc.), in combination with various AI learning types (pre-training, transfer learning, reinforcement learning, active learning, etc.) and input representations (1D SMILES, 2D graph, 3D shape,?binding site,?pharmacophore, etc.), to enable customized solutions for a given molecular design scenario. Besides the usual generation followed screening protocol, goal-directed molecule generation can also be conducted towards predefined goals, enhancing the efficiency of hit identification, lead finding, and lead optimization. We demonstrate the effectiveness of ID4Idea platform through case studies, showcasing customized solutions for different design tasks using various input information, such as binding pockets, pharmacophores, and compound representations. In addition, remaining challenges are discussed to unlock the full potential of AI models in drug discovery and pave the way for the development of novel therapeutics.

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期刊：Journal of Chemical Theory and Computation?2024, 20, 2, 799–818

作者：Bai Xue, Qingyi Yang, Qiaochu Zhang, Xiao Wan, Dong Fang, Xiaolu Lin, Guangxu Sun, Gianpaolo Gobbo, Fenglei Cao, Alan M. Mathiowetz, Benjamin J. Burke, Robert A. Kumpf, Brajesh K. Rai, Geoffrey P. F. Wood, Frank C. Pickard IV, Junmei Wang, Peiyu Zhang, Jian Ma, Yide Alan Jiang, Shuhao Wen, Xinjun Hou*, Junjie Zou*, Mingjun Yang*

時間：2023.12.29

Biomolecular simulations have become an essential tool in contemporary drug discovery, and molecular mechanics force fields (FFs) constitute its cornerstone. Developing a high quality and broad coverage general FF is a significant undertaking that requires substantial expert knowledge and computing resources, which is beyond the scope of general practitioners. Existing FFs originate from only a limited number of groups and organizations, and they either suffer from limited numbers of training sets, lower than desired quality because of oversimplified representations, or are costly for the molecular modeling community to access. To address these issues, in this work, we developed an AMBER-consistent small molecule FF with extensive chemical space coverage, and we provide Open Access parameters for the entire modeling community. To validate our FF, we carried out benchmarks of quantum mechanics (QM)/molecular mechanics conformer comparison and free energy perturbation calculations on several benchmark data sets. Our FF achieves a higher level of performance at reproducing QM energies and geometries than two popular open-source FFs, OpenFF2 and GAFF2. In relative binding free energy calculations for 31 protein–ligand data sets, comprising 1079 pairs of ligands, the new FF achieves an overall root-mean-square error of 1.19 kcal/mol for ΔΔG?and 0.92 kcal/mol for ΔG?on a subset of 463 ligands without bespoke fitting to the data sets. The results are on par with those of the leading commercial series of OPLS FFs.

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期刊：Journal of Chemical Information and Modeling?2023, 63, 16, 5341–5355

作者：Lin Wei, Min Xu, Zhiqiang Liu, Chongguo Jiang, Xiaohua Lin, Yaogang Hu, Xiaoming Wen, Rongfeng Zou, Chunwang Peng, Hongrui Lin, Guo Wang, Lijun Yang, Lei Fang*, Mingjun Yang, Peiyu Zhang

時間：2023.08.07

Computer-aided drug design (CADD), especially artificial intelligence-driven drug design (AIDD), is increasingly used in drug discovery. In this paper, a novel and efficient workflow for hit identification was developed within the?ID4Inno?drug discovery platform, featuring innovative artificial intelligence, high-accuracy computational chemistry, and high-performance cloud computing. The workflow was validated by discovering a few potent hit compounds (best IC₅₀?is ～0.80 μM) against PI5P4K-β, a novel anti-cancer target. Furthermore, by applying the tools implemented in?ID4Inno, we managed to optimize these hit compounds and finally obtained five hit series with different scaffolds, all of which showed high activity against PI5P4K-β. These results demonstrate the effectiveness of?ID4inno?in driving hit identification based on artificial intelligence, computational chemistry, and cloud computing.

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期刊：International Journal of Biological Macromolecules Volume 231,?15 March 2023, 123503

作者：Junqing Gong ^a, Zhaoyuan Wang ^a, Zhujuan Guo ^a, Lijuan Yao ^a, Chuanfang Zhao ^b, Sheng Lin ^b, Songling Ma ^b, Yingbai Shen ^a

^?aNational Engineering Research Center of Tree breeding and Ecological Restoration, College of Biological Sciences and Technology, Beijing Forestry University, No. 35, Qinghua East Road, Beijing 100083, PR China^bBeijing Jingtai Technology Co., Ltd., Beijing 100083, PR China

時間：2023.02.01

Evk (ethyl vinyl ketone) is a signal substance for plant defense, but little is known about how evk mediates stomatal closure. Through stomatal biology experiments, we found that evk can mediate stomatal closure, and stomatal closure is weakened when DORN1 (DOES NOT RESPOND TO NUCLEOTIDES 1) and GORK (GATED OUTWARDLY-RECTIFYING K+ CHANNEL) are mutated. In addition, it was found by non-invasive micro-test technology (NMT) that the K⁺?efflux mediated by evk was significantly weakened when DORN and GORK were mutated. Yeast two-hybrid (Y2H), firefly luciferase complementation imaging (LCI), and?in vitro?pull-down assays demonstrated that DORN1 and GORK could interact?in vitro?and?in vivo. It was found by molecular docking that evk could combine with MRP (Multidrug Resistance-associated Protein), thus affecting ATP transport, promoting eATP (extracellular ATP) concentration increase and realizing downstream signal transduction. Through inoculation of?botrytis cinerea, it was found that evk improved the antibacterial activity of?Arabidopsis thaliana. As revealed by reverse transcription quantitative PCR (RT-qPCR), the expression of defense related genes was enhanced by evk treatment. Evk is a potential green antibacterial drug.

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