HDAC6 detector: online application for evaluating compounds as potential histone deacetylase 6 inhibitors

• Published in: SAR and QSAR in environmental research Vol. 34; no. 8; pp. 619 - 637
• Main Authors: Tinkov, O.V., Grigorev, V.Y., Grigoreva, L.D., Osipov, V.N., Kolotaev, A.V., Khachatryan, D.S.
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 03-08-2023; Taylor & Francis Ltd
• Subjects: Apoptosis; Applications programs; Biological activity; Cell division; Histone deacetylase; Histones; Hydroxamic acids; Immune response; Immunosuppressive agents; Inhibitors; machine learning; molecular fingerprints; QSAR; Screening; Sensors; Streamlit; structural interpretation; Structure-activity relationships; Hydroxamic acids; machine learning; QSAR; Streamlit; structural interpretation; molecular fingerprints
• ISSN: 1062-936X; 1029-046X
• DOI: 10.1080/1062936X.2023.2244419

The HDAC6 (histone deacetylase 6) enzyme plays a key role in many biological processes, including cell division, apoptosis, and immune response. To date, HDAC6 inhibitors are being developed as effective drugs for the treatment of various diseases. In this work, adequate QSAR models of HDAC6 inhibitors are proposed. They are integrated into the developed application HDAC6 Detector, which is freely available at
https://ovttiras-hdac6-detector-hdac6-detector-app-yzh8y5.streamlit.app/
. The web application HDAC6 Detector can be used to perform virtual screening of HDAC6 inhibitors by dividing the compounds into active and inactive ones relative to the reference vorinostat compound (IC
50
 = 10.4 nM). The web application implements a structural interpretation of the developed QSAR models. In addition, the application can evaluate the compliance of a compound with Lipinski's rule. The developed models are used for virtual screening of a series of 12 new hydroxamic acids, namely, the derivatives of 3-hydroxyquinazoline-4(3H)-ones and 2-aryl-2,3-dihydroquinazoline-4(1H)-ones. In vitro evaluation of the inhibitory activity of this series of compounds against HDAC6 allowed us to confirm the results of virtual screening and to select promising compounds V-6 and V-11, the IC
50
of which is 0.99 and 0.81 nM, respectively.