2. Academic Validation
  3. Exploiting the tolerant region I of the non-nucleoside reverse transcriptase inhibitor (NNRTI) binding pocket. Part 2: Discovery of diarylpyrimidine derivatives as potent HIV-1 NNRTIs with high Fsp3 values and favorable drug-like properties

Exploiting the tolerant region I of the non-nucleoside reverse transcriptase inhibitor (NNRTI) binding pocket. Part 2: Discovery of diarylpyrimidine derivatives as potent HIV-1 NNRTIs with high Fsp3 values and favorable drug-like properties

  • Eur J Med Chem. 2021 Mar 5:213:113051. doi: 10.1016/j.ejmech.2020.113051.
Xiangyi Jiang 1,  Boshi Huang 2,  Fisayo A Olotu 3,  Jing Li 1,  Dongwei Kang 1,  Zhao Wang 1,  Erik De Clercq 4,  Mahmoud E S Soliman 5,  Christophe Pannecouque 6,  Xinyong Liu 7,  Peng Zhan 8
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 E Leigh Street, Richmond, VA, 23298, USA.
  • 3 Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.
  • 4 Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Leuven, B-3000, Belgium.
  • 5 Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa. Electronic address: Soliman@ukzn.ac.za.
  • 6 Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U. Leuven, Leuven, B-3000, Belgium. Electronic address: christophe.pannecouque@rega.kuleuven.be.
  • 7 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong, Province, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.
  • 8 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong, Province, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: zhanpeng1982@sdu.edu.cn.
PMID: 33279288 DOI: 10.1016/j.ejmech.2020.113051
Abstract

To yield potent HIV-1 non-nucleoside Reverse Transcriptase inhibitors (NNRTIs) with favorable drug-like properties, a series of novel diarylpyrimidine derivatives targeting the tolerant region I of the NNRTI binding pocket were designed, synthesized and biologically evaluated. The most active inhibitor 10c exhibited outstanding Antiviral activity against most of the viral panel, being about 2-fold (wild-type, EC50 = 0.0021 μM), 1.7-fold (K103N, EC50 = 0.0019 μM), and slightly more potent (E138K, EC50 = 0.0075 μM) than the NNRTI drug etravirine (ETR). Additionally, 10c was endowed with relatively low cytotoxicity (CC50 = 18.52 μM). More importantly, 10c possessed improved drug-like properties compared to those of ETR with an increased Fsp3 (Fraction of sp3 carbon atoms) value. Furthermore, the molecular dynamics simulation and molecular docking studies were implemented to reveal the binding mode of 10c in the binding pocket. Taken together, 10c is a promising lead compound that is worth further investigation.

Keywords

Diarylpyrimidine; Drug-like properties; Fsp(3); HIV-1 NNRTIs; Tolerant region I.

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