Towards the de novo Design of HIV-1 Protease Inhibitors based on Natural Products

In the world, the acquired immunodeficiency syndrome (AIDS) caused by the human immunode-ficiency virus (HIV) continues to be a public health problem. In 2020, 680,000 people died from HIV-related causes, and 1.5 million people were infected. Antiretrovirals are only a way to control HIV, not a cure as such, so effective treatment must be developed to control AIDS. However, de-veloping a drug is not an easy task. The enormous amount of work and financial invested. For this reason, it is highly convenient to employ computer-aided drug design methods, which can help to generate and identify novel molecules. Using the de novo design, new novel molecules can be de-veloped from scratch using fragments as building-blocks. In this work we develop a virtual focused compound library of HIV-1 viral protease inhibitors from natural product fragments. Natural products are characterized by a large diversity of functional groups, a large number of sp3 atoms, and chiral centers; and the pseudo-natural product is a combination of natural products fragments that conserve the desired structural characteristics from different natural products.由人类免疫缺陷病毒（human immunodeficiency virus, HIV）引发的获得性免疫缺陷综合征（acquired immunodeficiency syndrome, AIDS，即艾滋病）仍是全球范围内亟待解决的公共卫生问题。2020年，全球共有68万人因HIV相关病症离世，另有150万人新增感染。抗逆转录病毒药物仅能实现HIV的病情控制，无法实现根治，因此亟需开发高效治疗手段以遏制艾滋病的发展。然而，新药研发并非易事，需投入海量的人力与财力资源。鉴于此，计算机辅助药物设计（computer-aided drug design）方法的应用极具价值，该技术可助力新型分子的设计与筛选。借助分子从头设计（de novo design）技术，可从基础片段出发，以结构单元为基础从零开始构建全新的分子。本研究基于天然产物片段，构建了针对HIV-1病毒蛋白酶抑制剂（HIV-1 viral protease inhibitors）的虚拟聚焦化合物库。天然产物具有官能团多样性丰富、sp³杂化原子与手性中心占比高的结构特征；而伪天然产物（pseudo-natural product）则是将不同天然产物的优势结构片段进行组合，保留目标所需的结构特性。