Computational study of novel natural inhibitors targeting aminopeptidase N(CD13)

Junliang Ge,Bo Wu,Junan Ren,Xinhui Wang,Weihang Li,Zhongfeng Wang,Ziling Liu,Ye Cheng,Xing Su

doi:10.18632/aging.103155

Abstract

Objectives: To screen and identify ideal leading compounds from a drug library (ZINC15 database) with potential inhibition of aminopeptidase N(CD13) to contribute to medication design and development.Results: Two novel natural compounds, ZINC000000895551 and ZINC000014820583, from the ZINC15 database were found to have a higher binding affinity and more favorable interaction energy binding with CD13 with less rodent carcinogenicity, Ames mutagenicity, and non-inhibition with cytochrome P-450 2D6. Molecular dynamics simulation analysis suggested that the 2 complexes, ZINC000000895551-CD13 and ZINC000014820583-CD13, have favorable potential energy, and exist stably in the natural circumstances.Conclusion: This study discovered that ZINC000000895551 and ZINC000014820583 were ideal leading compounds to be inhibitions targeting to CD13. These compounds were selected as safe drug candidates as CD13 target medication design and improvement.Materials and Method: Potential inhibitors of CD13 were identified using a series of computer-aided structural and chemical virtual screening techniques. Structure-based virtual screening was carried out to calculate LibDock scores, followed by analyzing their absorption, distribution, metabolism, and excretion and toxicity predictions. Molecule docking was employed to reveal binding affinity between the selected compounds and CD13. Molecular dynamics simulation was applied to evaluate stability of the ligand-CD13 complex under natural environment.

Highlights

Cancer is a lethal condition ranking the second among all factors that cause human death in the world
CD13 could be upregulated by hypoxia, angiogenic factors such as vascular endothelial cell growth factor (VEGF), basic fibroblast growth factor, and type IV collagen facilitates the migration of these cells into the surrounding tissue [7]
This study provides lists of candidate compounds from the ZINC15 database and their pharmacologic properties, which could provide a solid foundation in developing CD13 inhibitor research

Summary

Introduction

Cancer is a lethal condition ranking the second among all factors that cause human death in the world. The treatment has evolved to include different modalities including surgery, chemotherapy, radiotherapy and www.aging-us.com immunotherapy [1, 2]. Despite these different treatment approaches, cancer has distinctive common characters including metastasis, adhesion and vascular hyperplasia. There is still a lack of a broad-spectrum approach to cancer treatment targeting these characters. [3,4,5] CD13 plays important roles in vascular endothelial morphogenesis during angiogenesis, through increasing the cellular adhesion to various adhesion molecules including type IV collagen, type I collagen and fibronectin [6]. The high levels of CD13 expressed on the surface of the cells may oppose the apoptosis of the leukemic cells, leading to the overgrowth of the cells [8]

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