Development of Novel Selective Pharmacophore for Tankyrase Inhibitors

Title:Development of Novel Selective Pharmacophore for Tankyrase Inhibitors

Volume: 14 Issue: 10

Author(s): Xin Qiao, Ting Ran, Yan-Min Zhang, Jing Pan, Ling-Feng Yin, Wei-Neng Zhou, Lu Zhu, Jun-Nan Zhao, Hai-Chun Liu, Shuai Lu, Tao Lu, Ya-Dong Chen*Yu-Lei Jiang*

Affiliation:

• Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198,China

• Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198,China

Keywords: Wnt pathway, tankyrases, cancer, selectivity, 3D-QSAR pharmacophore modeling, FTMap.

Abstract: Background: Tankyrases, members of PARP protein superfamily, are involved in many cellular processes and play key roles in Wnt signaling and in several diseases including cancers. During the past few years, there has been an increased interest in the development of selective smallmolecular tankyrase inhibitors.

Objective: The objective was to construct a novel selective pharmacophore model for tankyrase inhibitors.

Methods: In this paper, the novel selective pharmacophore model was constructed using a combination of computational methods, including molecular docking, protein-ligand interaction fingerprint (PLIF) similarity investigation, 3D-QSAR pharmacophore merging, binding site analysis like protein sequence alignment, SiteMap and FTMap.

Results: Within these analyses, a novel selective pharmacophore model was constructed. The two HY features were located in the induced pocket and the sub-pocket, respectively. The hydrogen bond acceptor (HBA) feature corresponding to Tyr1213 was located in the sub-pocket. To assess the reliability and validity of the pharmacophore, the model was then applied to screen two validation databases for highly selective tankyrase inhibitors. The high values of enrichment factor (32.61; 34.52) and receiver operating characteristic (ROC) score (0.853; 0.805) indicated the model performed fairly well at distinguishing the selective tankyrase inhibitors from putative inactive compounds. Furthermore, 12 highly selective inhibitors (10000-fold) were all ranked in the forefront of screening results.

Conclusion: The pharmacophore model reflects the most important binding requirements for the selective tankyrase inhibitors, and the results can provide new insights for design and discovery of novel tankyrase inhibitors with high selectivity.

Cite this article as:

Qiao Xin, Ran Ting, Zhang Yan-Min, Pan Jing, Yin Ling-Feng, Zhou Wei-Neng, Zhu Lu, Zhao Jun-Nan, Liu Hai-Chun, Lu Shuai, Lu Tao, Chen Ya-Dong*, Jiang Yu-Lei*, Development of Novel Selective Pharmacophore for Tankyrase Inhibitors, Letters in Drug Design & Discovery 2017; 14 (10) . https://dx.doi.org/10.2174/1570180814666170118151011

DOI https://dx.doi.org/10.2174/1570180814666170118151011	Print ISSN 1570-1808
Publisher Name Bentham Science Publisher	Online ISSN 1875-628X