聚焦领域：GPCRs
GPCRs对人类健康至关重要。
G蛋白偶联受体(GPCR)构成人类基因组中最大的膜蛋白家族, 已发现有826名成员。它们的作用几乎涵盖了所有生理机能，包括代谢、免疫系统调节、心率、行为和感觉系统，这意味着它们是重要的治疗靶点。迄今为止，目前约有475 种上市药物可作用于100 多个独特的GPCR。然而，还有 220 多种 GPCR 尚未作为临床靶点进行探索，这意味着具有广泛的治疗潜力等待发掘。
GPCR 本身就是具有挑战性的靶点
GPCR机制十分复杂。它们的主要作用是识别胞外物质（主要是配体）并跨膜向细胞内部传递信号。胞外配体与GPCR结合以诱导构象变化，从而影响下游信号传导。配体结合可在各种模式下激活下游路径，包括G-蛋白、β-抑制素和其他非G-蛋白转导体，从而产生生理和病理效应。
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GPCR 结构可视化十分复杂，使得基于GPCR 结构的药物发现充满挑战性。
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GPCR蛋白表达水平低且不稳定，给结构表征和药理学表征造成重大障碍。
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下游信号通路因多样性问题而激活非预期通路，增加了潜在脱靶的可能性。
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GPCR 结合位点之间的相似性不利于设计具有特异性受体选择性的药物。
硕迪解决方案
凭借在基于GPCR 结构的药物设计方面创造的无与伦比的记录，硕迪团队熟练地部署突破性的技术成果来应对这些挑战，以追求有创新性的小分子药物。在探索这些众所周知艰难的药物靶点方面，公司团队积累了深厚经验，其中包括公司创始人首次解决了人体GPCR晶体结构与扩散性配体相结合的问题。
公司平台
硕迪平台释放出GPCRs发展潜力。
我们的平台整合了多项突破性技术，旨在克服GPCR药物研发方面存在的历史局限性。
深入研究蛋白结构和动力学，助力智能药物设计发展。
我们基于结构的技术平台将受体结合相互作用的可视化与分子运动和信号转导的先进模拟技术相结合，从而可设计出具有理想结合性质和构象特征的分子药物，可精确诱导下游信号传导。
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由薛定谔软件赋能的领先计算化学平台
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结构技术，包括冷冻电镜和X射线晶体学
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先进的苗头化合物发现技术，包括DNA编码库（DEL）技术和亲和质谱筛选技术
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药物化学与药理学整合的实验平台
打造快速和高效的药物研发平台
公司旗下全资子公司倍勘生物(Basecamp Bio) 专注于早期药物研发和技术发展。倍勘生物在公司内部专有的药物发现工具基础上进行优化，从而实现在传统方法无法实现的规模下合成和筛选大量小分子候选药物。
我们采用迭代计算方法在合成和分析之前评估和优化设计小分子药物。相比传统药物发现，该方式可以加速先导化合物优化过程、降低开发成本并可能提高临床成功的可能性。
传统方法
倍勘平台
我们的最终目标：
有创新性的小分子药物。
凭借在基于结构的药物设计方面积累的丰富专业知识，我们可以设计出具有更强活性、特定信号响应和更优选择性的小分子药物，同时保持理想的药物特性。我们的目标是设计出具有类似生物活性和特异性的小分子药物，打破生物制剂固有限制的束缚。
早期药物发现合作伙伴
我们的药物发现引擎能够快速有效地开发临床药物。我们与倍勘生物合作，共同探索选择性合作伙伴关系，以攻克生物制药行业所追求的具有挑战性的细胞受体靶标。是否有兴趣与我们进行合作？ 立即联系我们。
为什么现在选择小分子药物?
鉴于在基于结构的药物发现方法方面取得的最新进展，我们现在可以设计定制药物，精确诱导下游信号传导效应，从而改善疾病。这些口服小分子药物目前可以改善患者体验，惠及更多患者，同时具有生物制剂的治疗活性。
出版物展示
了解过去20年奠定硕迪创新技术和方法的出版物。
Yang Yue, Lier Liu, Li-Jie Wu, Yiran Wu, Ling Wang, Fei Li, Junlin Liu, Gye-Won Han, Bo Chen, Xi Lin, Rebecca L Brouillette, Émile Breault, Jean-Michel Longpré, Songting Shi, Hui Lei, Philippe Sarret, Raymond C Stevens, Michael A Hanson, Fei Xu “Structural insight into apelin receptor-G protein stoichiometry” Nat Struct Mol Biol. 2022 Jul;29(7):688-697. doi: 10.1038/s41594-022-00797-5. Epub 2022 Jul 11.
December 6, 2022/by eallisonC. Martin, L.E. Gimenez, S.Y. Williams, Y. Jing, Y. Wu, C. Hollanders, O. Van der Poorten, S. Gonzalez, K. Van Holsbeeck, S. Previti, A. Lamouroux, S. Zhao, D. Tourwe, R.C. Stevens, R.D. Cone, S. Ballet “Structure based design of melanocortin 4 receptor ligands based on the SHU-9119-hMC4R cocrystal structure.” J. Med. Chem. 64, 357-369 (2021). doi: 10.1021/acs.jmedchem.0c01620.
February 13, 2021/by adminJ. Singla, K.L. White, R.C. Stevens, F. Abler “Assessment of scoring functions to rank the quality of 3D subtomogram clusters from cryo-electron tomography” J. Struct. Biol. Online 19 Mar (2021). doi: 10.1016/j.jsb.2021.107727.
February 13, 2021/by adminZ. Wang, T. Gurlo, A.V. Matveyenko, D. Elashoff, P. Wang, M. Rosenberger, J.A. Junge, R.C. Stevens, K.L. White, S.E. Fraser, P.C. Butler “Live-cell imaging of glucose-induced metabolic coupling of β and α cell metabolism in health and type 2 diabetes” Commun. Biol. 4, 594 (2021). doi: 10.1038/s42003-021-02113-1.
February 13, 2021/by adminF. Zhao, C. Zhang, Q. Zhou, K. Hang, X. Zou, Y. Chen, F. Wu, Q. Rao, A. Dai, W. Yin, D.D. Shen, Y. Zhang, T. Xia, R.C. Stevens, H.E. Xu, D. Yang, L. Zhao, M.W. Wang “Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor.” Elife 10, e68719 (2021). doi: 10.7554/eLife.68719.
February 13, 2021/by adminM. Audet, K. Villers, J. Velasquez, M. Chu, C. Hanson, R.C. Stevens “Small-scale approach for precrystallization screening in GPCR X-ray crystallography” Nat. Protoc. 15, 144-160 (2020). doi: 10.1038/s41596-019-0259-y.
February 13, 2020/by adminR. Lamichhane, J.J. Liu, K.L. White, V. Katritch, R.C. Stevens, K. Wüthrich, D.P. Millar “Biased signaling in the G-protein-coupled receptor β2AR is governed by conformational exchange kinetics” Structure 28, 371-377 (2020). doi: 10.1016/j.str.2020.01.001. PMC7213800.
February 13, 2020/by adminF. Wu, L. Yang, K. Hang, M. Laursen, L. Wu, G.W. Han, Q. Ren, N.K. Roed, G. Lin, M.A. Hanson, H. Jiang, M.W. Wang, S. Reedtz-Runge, G. Song, R.C. Stevens “Full-length human GLP-1 receptor structure without orthosteric ligands” Nat. Commun. 11, 1272 (2020). doi: 10.1038/s41467-020-14934-5. PMC7062719.
February 13, 2020/by adminJ. Yu, L.E. Gimenez, C.C. Hernandez, Y. Wu, A.H. Wein, G.W. Han, K. McClary, S.R. Mittal, K. Burdsall, B. Stauch, L. Wu, S.N. Stevens, A. Peisley, S.Y. Williams, V. Chen, G.L. Millhauser, S. Zhao, R.D. Cone, R.C. Stevens “Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding” Science 368, 428-433 (2020). online 24 April 2020. doi: 10.1126/science.aaz8995. PMC7567314.
February 13, 2020/by adminS. Zhao, B. Wu, R.C. Stevens “Advancing chemokine GPCR structure based drug discovery” Structure 27, 405-408 (2019). doi: 10.1016/j.str.2019.02.004
February 13, 2019/by adminYang Yue, Lier Liu, Li-Jie Wu, Yiran Wu, Ling Wang, Fei Li, Junlin Liu, Gye-Won Han, Bo Chen, Xi Lin, Rebecca L Brouillette, Émile Breault, Jean-Michel Longpré, Songting Shi, Hui Lei, Philippe Sarret, Raymond C Stevens, Michael A Hanson, Fei Xu “Structural insight into apelin receptor-G protein stoichiometry” Nat Struct Mol Biol. 2022 Jul;29(7):688-697. doi: 10.1038/s41594-022-00797-5. Epub 2022 Jul 11.
December 6, 2022/by eallisonC. Martin, L.E. Gimenez, S.Y. Williams, Y. Jing, Y. Wu, C. Hollanders, O. Van der Poorten, S. Gonzalez, K. Van Holsbeeck, S. Previti, A. Lamouroux, S. Zhao, D. Tourwe, R.C. Stevens, R.D. Cone, S. Ballet “Structure based design of melanocortin 4 receptor ligands based on the SHU-9119-hMC4R cocrystal structure.” J. Med. Chem. 64, 357-369 (2021). doi: 10.1021/acs.jmedchem.0c01620.
February 13, 2021/by adminJ. Singla, K.L. White, R.C. Stevens, F. Abler “Assessment of scoring functions to rank the quality of 3D subtomogram clusters from cryo-electron tomography” J. Struct. Biol. Online 19 Mar (2021). doi: 10.1016/j.jsb.2021.107727.
February 13, 2021/by adminZ. Wang, T. Gurlo, A.V. Matveyenko, D. Elashoff, P. Wang, M. Rosenberger, J.A. Junge, R.C. Stevens, K.L. White, S.E. Fraser, P.C. Butler “Live-cell imaging of glucose-induced metabolic coupling of β and α cell metabolism in health and type 2 diabetes” Commun. Biol. 4, 594 (2021). doi: 10.1038/s42003-021-02113-1.
February 13, 2021/by adminF. Zhao, C. Zhang, Q. Zhou, K. Hang, X. Zou, Y. Chen, F. Wu, Q. Rao, A. Dai, W. Yin, D.D. Shen, Y. Zhang, T. Xia, R.C. Stevens, H.E. Xu, D. Yang, L. Zhao, M.W. Wang “Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor.” Elife 10, e68719 (2021). doi: 10.7554/eLife.68719.
February 13, 2021/by adminM. Audet, K. Villers, J. Velasquez, M. Chu, C. Hanson, R.C. Stevens “Small-scale approach for precrystallization screening in GPCR X-ray crystallography” Nat. Protoc. 15, 144-160 (2020). doi: 10.1038/s41596-019-0259-y.
February 13, 2020/by adminR. Lamichhane, J.J. Liu, K.L. White, V. Katritch, R.C. Stevens, K. Wüthrich, D.P. Millar “Biased signaling in the G-protein-coupled receptor β2AR is governed by conformational exchange kinetics” Structure 28, 371-377 (2020). doi: 10.1016/j.str.2020.01.001. PMC7213800.
February 13, 2020/by adminF. Wu, L. Yang, K. Hang, M. Laursen, L. Wu, G.W. Han, Q. Ren, N.K. Roed, G. Lin, M.A. Hanson, H. Jiang, M.W. Wang, S. Reedtz-Runge, G. Song, R.C. Stevens “Full-length human GLP-1 receptor structure without orthosteric ligands” Nat. Commun. 11, 1272 (2020). doi: 10.1038/s41467-020-14934-5. PMC7062719.
February 13, 2020/by adminJ. Yu, L.E. Gimenez, C.C. Hernandez, Y. Wu, A.H. Wein, G.W. Han, K. McClary, S.R. Mittal, K. Burdsall, B. Stauch, L. Wu, S.N. Stevens, A. Peisley, S.Y. Williams, V. Chen, G.L. Millhauser, S. Zhao, R.D. Cone, R.C. Stevens “Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding” Science 368, 428-433 (2020). online 24 April 2020. doi: 10.1126/science.aaz8995. PMC7567314.
February 13, 2020/by adminS. Zhao, B. Wu, R.C. Stevens “Advancing chemokine GPCR structure based drug discovery” Structure 27, 405-408 (2019). doi: 10.1016/j.str.2019.02.004
February 13, 2019/by adminA. Batyuk, L. Galli, A. Ishchenko, G.W. Han, C. Gati, P.A. Popov, M.Y. Lee, B. Stauch, T.A. White, A. Barty, A. Aquila, M.S. Hunter, M. Liang, S. Boutet, M. Pu, Z.J. Liu, G. Nelson, D. James, C. Li, Y. Zhao, J.C. Spence, W. Liu, P. Fromme, V. Katritch, U. Weierstall, R.C. Stevens, V. Cherezov “Native phasing of x-ray free-electron laser data for a G protein-coupled receptor” Sci. Adv. 2, e1600292 (2016). PMC5035125.
February 13, 2016/by adminT. Hua, K. Vemuri, M. Pu, L. Qu, G.W. Han, Y. Wu, S. Zhao, W. Shui, S. Li, A. Korde, R.B. Laprairie, E.L. Stahl, J.-H. Ho, N. Zvonok, H. Zhou, I. Kufareva, B. Wu, Q. Zhao, M.A. Hanson, L.M. Bohn, A. Makriyannis, R.C. Stevens, Z.-J. Liu “Crystal structure of the human cannabinoid receptor CB1” Cell 167, 750-762 (2016). PMC5322940.
February 13, 2016/by adminM.T. Eddy, T. Didenko, R.C. Stevens, K. Wüthrich “2-Adrenergic receptor conformational response to fusion protein in the third intracellular loop” Structure 24, 1-8 (2016). PMC5144828.
February 13, 2016/by adminY. Zheng, L. Qin, N.V. Ortiz Zacarias, H. de Vries, G.W. Han, M. Gustavsson, M. Dabros, C. Zhao, R. Cherney, P. Carter, D. Stamos, R. Abagyan, V. Cherezov, R.C. Stevens, A.P. IJzerman, L.H. Heitman, A. Tebben, I. Kufareva, T.M. Handel “Structure of CC Chemokine Receptor 2 with Orthosteric and Allosteric Antagonists” Nature 540, 458-461 (2016). PMC5159191.
February 13, 2016/by adminD. Yang, C. de Graaf, L. Yang, G. Song, A. Dai, X. Cai, Y. Feng, S. Reedtz-Runge, M.A. Hanson, H. Yang, H. Jiang, R.C. Stevens, M.W. Wang “Structural determinants of binding the seven-transmembrane domain of the glucagon-like peptide-1 receptor” J. Biol. Chem. 291, 12991-13004 (2016). PMC4933217.
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