Molecular Docking Studies of a Cyclic Octapeptide-Cyclosaplin from Sandalwood.

Mishra Mishra,Dey Dey

doi:10.3390/biom9110740

Abstract

Natural products from plants, such as chemopreventive agents, attract huge attention because of their low toxicity and high specificity. The rational drug design in combination with structure-based modeling and rapid screening methods offer significant potential for identifying and developing lead anticancer molecules. Thus, the molecular docking method plays an important role in screening a large set of molecules based on their free binding energies and proposes structural hypotheses of how the molecules can inhibit the target. Several peptide-based therapeutics have been developed to combat several health disorders, including cancers, metabolic disorders, heart-related diseases, and infectious diseases. Despite the discovery of hundreds of such therapeutic peptides however, only few peptide-based drugs have made it to the market. Moreover, the in silico activities of cyclic peptides towards molecular targets, such as protein kinases, proteases, and apoptosis related proteins have not been extensively investigated. In this study, we explored the in silico kinase and protease inhibitor potentials of cyclosaplin, and studied the interactions of cyclosaplin with other apoptosis-related proteins. Previously, the structure of cyclosaplin was elucidated by molecular modeling associated with dynamics that were used in the current study as well. Docking studies showed strong affinity of cyclosaplin towards cancer-related proteins. The binding affinity closer to 10 kcal/mol indicated efficient binding. Cyclosaplin showed strong binding affinities towards protein kinases such as EGFR, VEGFR2, PKB, and p38, indicating its potential role in protein kinase inhibition. Moreover, it displayed strong binding affinity to apoptosis-related proteins and revealed the possible role of cyclosaplin in apoptotic cell death. The protein–ligand interactions using LigPlot displayed some similar interactions between cyclosaplin and peptide-based ligands, especially in case of protein kinases and a few apoptosis related proteins. Thus, the in silico analyses gave the insights of cyclosaplin being a potential apoptosis inducer and protein kinase inhibitor.

Highlights

Cancer is a well-recognized global health problem responsible for ∼7.6 million deaths (∼13% of all deaths) worldwide, which is expected to rise to 13.1 million by 2030 (WHO, 2012)
The ligand structures were drawn in CycloPsWeb or downloaded from PubChem and converted to pdb format using Open Babel and modeled using GROMACS and MODELLER 9.2 program along with cyclosaplin (Table 2)
We previously showed the structure–activity relationship for epidermal growth factor’s receptor kinase domain (EGFR) kinase with cyclosaplin [11], but in the present study, we demonstrated the possible interactions between protein and ligand with key amino acid residues involved in such interactions

Summary

Introduction

Cancer is a well-recognized global health problem responsible for ∼7.6 million deaths (∼13% of all deaths) worldwide, which is expected to rise to 13.1 million by 2030 (WHO, 2012). Despite the advancements in the field of cancer research, there is still an urgency to discover and develop anti-cancer therapeutics. Natural products are of particular interest as chemopreventive agents because of their low toxicities and potential efficacies [1]. The conventional drug discovery techniques are time consuming and expensive processes [2]. Rational drug design in combination with structure based modeling and rapid screening methods offer significant potential for identifying and developing lead anticancer molecules. The use of the molecular docking method addresses deducing the ligand binding sites

Methods

Results

Discussion

Conclusion