Development of PROTACs using computational approaches

Jingxuan Ge; Chang-Yu Hsieh; Meijing Fang; Huiyong Sun; Tingjun Hou

doi:10.1016/j.tips.2024.10.006

Development of PROTACs using computational approaches

Trends Pharmacol Sci. 2024 Nov 19:S0165-6147(24)00216-5. doi: 10.1016/j.tips.2024.10.006. Online ahead of print.

Authors

Jingxuan Ge¹, Chang-Yu Hsieh², Meijing Fang³, Huiyong Sun⁴, Tingjun Hou⁵

Affiliations

¹ College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China; CarbonSilicon AI Technology Company Ltd, Hangzhou 310018, Zhejiang, China.
² College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China.
³ Polytechnic Institute, Zhejiang University, Hangzhou 310058, Zhejiang, China.
⁴ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, Jiangsu, China. Electronic address: huiyongsun@cpu.edu.cn.
⁵ College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, China; Polytechnic Institute, Zhejiang University, Hangzhou 310058, Zhejiang, China. Electronic address: tingjunhou@zju.edu.cn.

PMID: 39567313
DOI: 10.1016/j.tips.2024.10.006

Abstract

Proteolysis-targeting chimeras (PROTACs) are drugs designed to degrade target proteins via the ubiquitin-proteasome system. With the application of computational biology/chemistry technique in drug design, numerous computer-aided drug design and artificial intelligence (AI)-driven drug design (CADD/AIDD) methods have recently emerged to facilitate the development of PROTAC drugs. We systematically review the role of in silico tools in PROTAC drug design, emphasizing how computational software can model PROTAC action and structure, predict activity, and assist in molecule design. We also discuss current challenges in the rational design of PROTACs from an in silico perspective, such as deviations from small-molecule druggability and the limited availability of training data. We provide an overview of recent discoveries and emerging research in this field, and discuss their potential impact on PROTAC design strategies.

Keywords: AIDD; CADD; MD simulation; PROTAC design; structure modeling.

Publication types

Review