Molecular Transformers: Adaptive Multitarget Ligands for Esterase-Induced Transition from Analgesics to Anesthetics,Journal of Medicinal Chemistry

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Molecular Transformers: Adaptive Multitarget Ligands for Esterase-Induced Transition from Analgesics to Anesthetics
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-07-16 , DOI: 10.1021/acs.jmedchem.4c01044
Tianguang Huang ₁ , Chi Song ₁ , Yuhao Chen ₂ , Yu Gan ₁ , Shilong Hu ₁ , Ao Hai ₁ , Wencheng Liu ₁ , Ting Kang ₁ , Yi Zhao ₁ , Zhuang Miao ₁ , Xing Wang ₂ , Yihang Fu ₃ , Bowen Ke ₁

Affiliation

Multitarget strategies are essential in addressing complex diseases, yet developing multitarget-directed ligands (MTDLs) is particularly challenging when aiming to engage multiple therapeutic targets across different tissues. Here, we present a molecular transformer strategy, enhancing traditional MTDLs. By utilizing esterase-driven hydrolysis, this approach mimics the adaptive nature of transformers for enabling molecules to modify their pharmacological effects in response to the biological milieu. By virtual screening and biological evaluation, we identified KGP-25, a novel compound initially targeting the voltage-gated sodium channel 1.8 (Na_v1.8) in the peripheral nervous system (PNS) for analgesia, and later the γ-aminobutyric acid subtype A receptor (GABA_A) in the central nervous system (CNS) for general anesthesia. Our findings confirm KGP-25’s dual efficacy in cellular and animal models, effectively reducing opioid-related side effects. This study validates the molecular transformer approach in drug design and highlights its potential to overcome the limitations of conventional MTDLs, paving new avenues in innovative therapeutic strategies.

中文翻译：

分子转化器：用于酯酶诱导的从镇痛药到麻醉药转变的自适应多靶点配体

多靶点策略对于解决复杂疾病至关重要，但当旨在参与不同组织的多个治疗靶点时，开发多靶点定向配体（MTDL）尤其具有挑战性。在这里，我们提出了一种分子转化策略，增强了传统的 MTDL。通过利用酯酶驱动的水解，这种方法模仿了变压器的适应性，使分子能够根据生物环境改变其药理作用。通过虚拟筛选和生物学评估，我们鉴定出了 KGP-25，这是一种新型化合物，最初针对周围神经系统 (PNS) 中的电压门控钠通道 1.8 (Na _v 1.8) 进行镇痛，后来又针对γ-氨基丁酸 A 亚型中枢神经系统 (CNS) 中的受体 (GABA _A ) 用于全身麻醉。我们的研究结果证实了 KGP-25 在细胞和动物模型中的双重功效，可有效减少阿片类药物相关的副作用。这项研究验证了药物设计中的分子转化方法，并强调了其克服传统 MTDL 局限性的潜力，为创新治疗策略开辟了新途径。

更新日期：2024-07-16

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