title: Identifying Novel Type ZBGs and Nonhydroxamate HDAC Inhibitors Through a SVM Based Virtual Screening Approach.
abstract: Histone deacetylase inhibitors (HDACi) have been successfully used for the treatment of cancers and other diseases. Search for novel type ZBGs and development of non-hydroxamate HDACi has become a focus in current research. To complement this, it is desirable to explore a virtual screening (VS) tool capable of identifying different types of potential inhibitors from large compound libraries with high yields and low false-hit rates similar to HTS. This work explored the use of support vector machines (SVM) combined with our newly developed putative non-inhibitor generation method as such a tool. SVM trained by 702 pre-2008 hydroxamate HDACi and 64334 putative non-HDACi showed good yields and low false-hit rates in cross-validation test and independent test using 220 diverse types of HDACi reported since 2008. The SVM hit rates in scanning 13.56 M PubChem and 168K MDDR compounds are comparable to HTS rates. Further structural analysis of SVM virtual hits suggests its potential for identification of non-hydroxamate HDACi. From this analysis, a series of novel ZBG and cap groups were proposed for HDACi design.
authors.affiliation: Bioinformatics and Drug Design Group, Department of Pharmacy, National University of Singapore, Blk S16,Level 8, 3 Science Drive 2, Singapore 117543 phone: 65-6874-6877, fax: 65-6774-6756.
authors.forename: X H
authors.initials: XH
authors.lastname: Liu
authors.affiliation: Institute of Materials Research and Engineering, A*STAR, 3 Research Link, Singapore 117602.
authors.forename: H Y
authors.initials: HY
authors.lastname: Song
authors.affiliation: Bioinformatics and Drug Design Group, Department of Pharmacy, National University of Singapore, Blk S16,Level 8, 3 Science Drive 2, Singapore 117543 phone: 65-6874-6877, fax: 65-6774-6756.
authors.forename: J X
authors.initials: JX
authors.lastname: Zhang
authors.affiliation: Bioinformatics and Drug Design Group, Department of Pharmacy, National University of Singapore, Blk S16,Level 8, 3 Science Drive 2, Singapore 117543 phone: 65-6874-6877, fax: 65-6774-6756.
authors.forename: B C
authors.initials: BC
authors.lastname: Han
authors.affiliation: Bioinformatics and Drug Design Group, Department of Pharmacy, National University of Singapore, Blk S16,Level 8, 3 Science Drive 2, Singapore 117543 phone: 65-6874-6877, fax: 65-6774-6756.
authors.forename: X N
authors.initials: XN
authors.lastname: Wei
authors.affiliation: Bioinformatics and Drug Design Group, Department of Pharmacy, National University of Singapore, Blk S16,Level 8, 3 Science Drive 2, Singapore 117543 phone: 65-6874-6877, fax: 65-6774-6756.
authors.forename: X H
authors.initials: XH
authors.lastname: Ma
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543.
authors.forename: W K
authors.initials: WK
authors.lastname: Cui
authors.affiliation: Bioinformatics and Drug Design Group, Department of Pharmacy, National University of Singapore, Blk S16,Level 8, 3 Science Drive 2, Singapore 117543 phone: 65-6874-6877, fax: 65-6774-6756. phacyz@nus.edu.sg.
authors.forename: Y Z
authors.initials: YZ
authors.lastname: Chen
keywords: Computer aided drug design; Drug design; HDAC; In silico modeling; Inhibitors; Machine learning; Nonhydroxamate; Support vector machine; Virtual screening; Zinc binding group