Structure based pharmacophore modeling, virtual screening, molecular docking and ADMET approaches for identification of natural anti-cancer agents targeting XIAP protein

Mohiuddin Ahmed Bhuiyan,Mohammed M. Rahman,Istiak Ahmed,Firoz A. Dain Md Opo,Foysal Ahammad,Abdullah M. Asiri

doi:10.1038/s41598-021-83626-x

Abstract

X-linked inhibitor of apoptosis protein (XIAP) is a member of inhibitor of apoptosis protein (IAP) family responsible for neutralizing the caspases-3, caspases-7, and caspases-9. Overexpression of the protein decreased the apoptosis process in the cell and resulting development of cancer. Different types of XIAP antagonists are generally used to repair the defective apoptosis process that can eliminate carcinoma from living bodies. The chemically synthesis compounds discovered till now as XIAP inhibitors exhibiting side effects, which is making difficulties during the treatment of chemotherapy. So, the study has design to identifying new natural compounds that are able to induce apoptosis by freeing up caspases and will be low toxic. To identify natural compound, a structure-based pharmacophore model to the protein active site cavity was generated following by virtual screening, molecular docking and molecular dynamics (MD) simulation. Initially, seven hit compounds were retrieved and based on molecular docking approach four compounds has chosen for further evaluation. To confirm stability of the selected drug candidate to the target protein the MD simulation approach were employed, which confirmed stability of the three compounds. Based on the finding, three newly obtained compounds namely Caucasicoside A (ZINC77257307), Polygalaxanthone III (ZINC247950187), and MCULE-9896837409 (ZINC107434573) may serve as lead compounds to fight against the treatment of XIAP related cancer, although further evaluation through wet lab is necessary to measure the efficacy of the compounds.

Highlights

Hepatocellular carcinoma (HCC) is one of the most predominant type of primary liver cancer that has ranked fourth most common cause of cancer-related death worldwide[1,2]
To minimize adverse effects caused for higher binding affinity, antagonist molecules having the lower micromolar affinity to the X-linked inhibitor of apoptosis protein (XIAP)-BIR2 domain is urgently need to d evelop[11,12]
This study focused mainly on computer aided drug design process like structure-based pharmacophore modeling, virtual screening, ADMET, molecular docking and dynamic simulation approaches to identify the possible natural antagonist against XIAP protein to treat the cancer

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most predominant type of primary liver cancer that has ranked fourth most common cause of cancer-related death worldwide[1,2]. Few important side effects have been observed in the case of developing of these compounds, SMAC/Diablo protein able to bind all BIR domains of several IAP most of are with cIAP1 and cIAP2 lead to the toxic effect or adverse effects due to the higher affinity of binding. In CADD approach, structure and ligand-based pharmacophore model can able to identify similar active molecules against specific target protein, where binding affinity of a large scale compound with target macromolecule can be evaluate by in-silico molecular docking p rocess[15]. This study focused mainly on computer aided drug design process like structure-based pharmacophore modeling, virtual screening, ADMET, molecular docking and dynamic simulation approaches to identify the possible natural antagonist against XIAP protein to treat the cancer

Methods

Discussion

Conclusion