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.

当前，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）仍是全球亟待解决的公共卫生难题。2020年，全球共有68万人死于HIV相关病症，另有150万人新增HIV感染。抗逆转录病毒药物仅能实现HIV的病情控制，而非真正意义上的治愈手段，因此亟需开发高效治疗方案以遏制艾滋病疫情。然而，新药研发绝非易事，需投入海量人力与财力资源。正因如此，采用计算机辅助药物设计（computer-aided drug design, CADD）方法成为极具优势的选择，该技术可助力新型分子的生成与筛选识别。借助从头分子设计（de novo design）技术，可通过以分子片段作为构建模块的方式，从零开始开发全新分子。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杂化原子占比高以及手性中心众多的结构特征；而伪天然产物则是将不同天然产物的优势结构片段进行组合，保留目标天然产物的核心结构特性。