title: Discovery of novel inhibitors disrupting HIF-1α/von Hippel-Lindau interaction through shape-based screening and cascade docking.
abstract: Major research efforts have been devoted to the discovery and development of new chemical entities that could inhibit the protein-protein interaction between HIF-1αand the von Hippel-Lindau protein (pVHL), which serves as the substrate recognition subunit of an E3 ligase and is regarded as a crucial drug target in cancer, chronic anemia, and ischemia. Currently there is only one class of compounds available to interdict the HIF-1α/pVHL interaction, urging the need to discover chemical inhibitors with more diversified structures. We report here a strategy combining shape-based virtual screening and cascade docking to identify new chemical scaffolds for the designing of novel inhibitors. Based on this strategy, nine active hits have been identified and the most active hit, 9 (ZINC13466751), showed comparable activity to pVHL with an IC50 of 2.0 ± 0.14 µM, showing the great potential of utilizing these compounds for further optimization and serving as drug candidates for the inhibition of HIF-1α/von Hippel-Lindau interaction.
authors.affiliation: Department of Medicinal Chemistry, Nanjing University of Chinese Medicine , Nanjing , China.
authors.forename: Xin
authors.initials: X
authors.lastname: Xue
authors.affiliation: Department of Pharmacy, Nanjing Health-Innovating Biotechnology Co., Ltd. , Nanjing , China.
authors.forename: Ning-Yi
authors.initials: NY
authors.lastname: Zhao
authors.affiliation: Department of Medicinal Chemistry, Nanjing University of Chinese Medicine , Nanjing , China.
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Yu
authors.affiliation: Department of Chemistry and Biochemistry, Ohio State University , Columbus , OH , United States.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Division of Pharmacology, College of Pharmacy, Ohio State University , Columbus , OH , United States.
authors.forename: Chen
authors.initials: C
authors.lastname: Kang
authors.affiliation: Department of Medicinal Chemistry, Nanjing University of Chinese Medicine , Nanjing , China.
authors.forename: Qiong-Bin
authors.initials: QB
authors.lastname: Huang
authors.affiliation: Department of Medicinal Chemistry, China Pharmaceutical University , Nanjing , China.
authors.forename: Hao-Peng
authors.initials: HP
authors.lastname: Sun
authors.affiliation: Department of Medicinal Chemistry, Nanjing University of Chinese Medicine , Nanjing , China.
authors.forename: Xiao-Long
authors.initials: XL
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, Nanjing University of Chinese Medicine , Nanjing , China.
authors.forename: Nian-Guang
authors.initials: NG
authors.lastname: Li
keywords: Cross-docking; HIF-1α/pVHL interaction; Native-docking; Protein–protein interaction; Shape-based screen