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Structure-Based Drug Design of Small Molecule Peptide Deformylase Inhibitors to Treat Cancer.

ABSTRACT: Human peptide deformylase (HsPDF) is an important target for anticancer drug discovery. In view of the limited HsPDF, inhibitors were reported, and high-throughput virtual screening (HTVS) studies based on HsPDF for developing new PDF inhibitors remain to be reported. We reported here on diverse small molecule inhibitors with excellent anticancer activities designed based on HTVS and molecular docking studies using the crystal structure of HsPDF. The compound M7594_0037 exhibited potent anticancer activities against HeLa, A549 and MCF-7 cell lines with IC50s of 35.26, 29.63 and 24.63 ?M, respectively. Molecular docking studies suggested that M7594_0037 and its three derivatives could interact with HsPDF by several conserved hydrogen bonds. Moreover, the pharmacokinetic and toxicity properties of M7594_0037 and its derivatives were predicted using the OSIRIS property explorer. Thus, M7594_0037 and its derivatives might represent a promising scaffold for the further development of novel anticancer drugs.

SUBMITTER: Gao J

PROVIDER: S-EPMC6273975 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Structure-Based Drug Design of Small Molecule Peptide Deformylase Inhibitors to Treat Cancer.

Gao Jian J Wang Tao T Qiu Shengzhi S Zhu Yasheng Y Liang Li L Zheng Youguang Y

Molecules (Basel, Switzerland) 20160323 4

Human peptide deformylase (HsPDF) is an important target for anticancer drug discovery. In view of the limited HsPDF, inhibitors were reported, and high-throughput virtual screening (HTVS) studies based on HsPDF for developing new PDF inhibitors remain to be reported. We reported here on diverse small molecule inhibitors with excellent anticancer activities designed based on HTVS and molecular docking studies using the crystal structure of HsPDF. The compound M7594_0037 exhibited potent anticanc ...[more]

PMID: 27023495

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Project description:BACKGROUND:Conventional de novo drug design is costly and time consuming, making it accessible to only the best resourced research organizations. An emergent approach to new drug development is drug repurposing, in which compounds that have already gone through some level of clinical testing are examined for efficacy against diseases divergent than their original application. Repurposing of existing drugs circumvents the time and considerable cost of early stages of drug development, and can be accelerated by using software to screen existing chemical databases to identify suitable drug candidates. RESULTS:Small-molecule Peptide-Influenced Drug Repurposing (SPIDR) was developed to identify small molecule drugs that target a specific receptor by exploring the conformational binding space of peptide ligands. SPIDR was tested using the potent and selective 16-amino acid peptide ?-conotoxin MII ligand and the ?3?2-nicotinic acetylcholine receptor (nAChR) isoform. SPIDR incorporates a genetic algorithm-based, heuristic search procedure, which was used to explore the ligand binding domain of the ?3?2-nAChR isoform using a library consisting of 640,000 ?-conotoxin MII peptide analogs. The peptides that exhibited the highest affinity for ?3?2-nAChR were used as models for a small-molecule structure similarity search of the PubChem Compound database. SPIDR incorporates the SimSearcher utility, which generates shape distribution signatures of molecules and employs multi-level K-means clustering to insure fast database queries. SPIDR identified non-peptide drugs with estimated binding affinities nearly double that of the native ?-conotoxin MII peptide. CONCLUSIONS:SPIDR has been generalized and integrated into DockoMatic v 2.1. This software contains an intuitive graphical interface for peptide mutant screening workflow and facilitates mapping, clustering, and searching of local molecular databases, making DockoMatic a valuable tool for researchers in drug design and repurposing.

Dataset Information

Structure-Based Drug Design of Small Molecule Peptide Deformylase Inhibitors to Treat Cancer.

Publications

Structure-Based Drug Design of Small Molecule Peptide Deformylase Inhibitors to Treat Cancer.

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