PDF(Pubmed)
Abstract：
Drug discovery and development constitute a laborious and costly undertaking. The success of a drug hinges not only good efficacy but also acceptable absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties. Overall, up to 50% of drug development failures have been contributed from undesirable ADMET profiles. As a multiple parameter objective, the optimization of the ADMET properties is extremely challenging owing to the vast chemical space and limited human expert knowledge. In this study, a freely available platform called Chemical Molecular Optimization, Representation and Translation (ChemMORT) is developed for the optimization of multiple ADMET endpoints without the loss of potency (https://cadd.nscc-tj.cn/deploy/chemmort/). ChemMORT contains three modules: Simplified Molecular Input Line Entry System (SMILES) Encoder, Descriptor Decoder and Molecular Optimizer. The SMILES Encoder can generate the molecular representation with a 512-dimensional vector, and the Descriptor Decoder is able to translate the above representation to the corresponding molecular structure with high accuracy. Based on reversible molecular representation and particle swarm optimization strategy, the Molecular Optimizer can be used to effectively optimize undesirable ADMET properties without the loss of bioactivity, which essentially accomplishes the design of inverse QSAR. The constrained multi-objective optimization of the poly (ADP-ribose) polymerase-1 inhibitor is provided as the case to explore the utility of ChemMORT.
摘要：
药物发现和开发是一项费力且昂贵的工作。药物的成功不仅取决于良好的疗效，还取决于可接受的吸收，分布，新陈代谢，消除,和毒性（ADMET）特性。总的来说,多达50％的药物开发失败是由不良的ADMET概况造成的。作为多参数目标，由于巨大的化学空间和有限的人类专业知识，ADMET特性的优化极具挑战性。在这项研究中,一个叫做化学分子优化的免费平台，表示和翻译（ChemMORT）是为优化多个ADMET端点而不损失效力而开发的（https：//cadd。nscc-tj.cn/deploy/chemmort/)。ChemMORT包含三个模块：简化分子输入线输入系统（SMILES）编码器，描述符解码器和分子优化器。SMILES编码器可以生成具有512维向量的分子表示，并且描述符解码器能够高精度地将上述表示转换为相应的分子结构。基于可逆分子表示和粒子群优化策略,分子优化器可用于有效优化不需要的ADMET特性，而不会损失生物活性，基本上完成了逆QSAR的设计。提供了聚（ADP-核糖）聚合酶1抑制剂的约束多目标优化，以探索ChemMORT的实用性。
