Full Length Research Article
Identification of phytochemicals as potential inhibitors against E6 protein of High-Risk Human Papillomavirus 16(HPV 16) via In-Silico Structure-Based Virtual Screening Approach
Arshad Jamal
Adv. life sci., vol. 10, no. 3, pp. 498-504, September 2023
*- Corresponding Author: Arshad Jamal (arshadjamalus@yahoo.com)
Authors' Affiliations
[Date Received: 19/06/2023; Date Revised: 12/09/2023; Date Published: 30/09/2023]
Abstract
Introduction
Methods
Results
Discussion
References
Abstract
Background: The human papillomavirus (HPV) is a potentially fatal infection and the most common cause of cancer related feminine mortality around the world, thus requiring the design of anticancer drugs. The E6 oncoprotein is one of the most investigated therapeutic targets for cancer treatment. E6 oncoprotein plays a major role in tumor progression and cell immortalization. The E6 protein leads to the degradation of tumor suppressor protein P53 via interacting with E6 binding protein E6AP. Therefore, inhibiting the E6 protein can be a potential target for HPV.
Methods: In this study we performed virtual screening of 2296 phytochemicals library from MPD3 database against E6 protein.
Results: Three compounds were picked out as potential inhibitors. These compounds were selected considering their binding energy and hydrogen bond interactions. Further to verify the stability of the docked complexes 100ns molecular dynamics simulations were carried out.
Conclusion: Keeping in view the numerous analyses, we suggest that the potential three compounds could prove relevancy regarding the anti-HPV therapeutic advancements.
Keywords: Human Papillomavirus; Anticancer Drugs; E6 Oncoprotein; Phytochemicals; Virtual Screening; Molecular Dynamics Simulations
Introduction
Human Papillomavirus (HPV) is a highly contagious and commonly sexually transmitted human pathogen. HPVs are DNA viruses that infect and reproduce in keratinized and mucosal epithelia, resulting in unusual hyperplastic lesions[1]. HPV consists of two kinds of genes, which includes early gene (E) and late genes (L) [2] having different roles such as regulation of the replication process, virus assembly and development of a tumor or cancerous Lesions [3]. Most of HPV genotypes which predominantly cause benign skin warts and anogenital lesions are considered as low-risk. Laryngo bronchial systems and papillomatosis are also caused by harmless HPV genotypes. Whilst the most dangerous HPV genotypes like HPV_16 and HPV-18 are predominantly responsible for causing cervical cancer and urogenital malignancies [4]. HPV is responsible for more than 5% of all malignancies in the world, such as all cervical cancers and oropharyngeal cancers [5, 6]. Regardless of considerably lower cervical cancer incidence in developed countries with established screening programs, cervical cancer is considered one of the highest reasons of cancer mediated mortality in female globally, owing to a lack of resources. HPV-related oropharyngeal cancer is just one of five malignancies in the United States that has increased in incidence since 1975 and has now surpassed the cervix as the most prevalent site of HPV-related cancer [7]. Genome of HPV encodes six early proteins E1, E2, E4, E5, E6 and E7 as well as two late proteins such as L1 and L2. However, E6 and E7 viral proteins have been identified as essential participants in the production and maintenance of HPV-related cervical cancer [5]. HPV oncoproteins such as E6 act by binding to p53 protein, as a result triggering degradation via proteasomes [8].
The HPV E6 protein is one of three oncoproteins encoded by the virus. It has been implicated a powerful oncogene and has also suggested for its role in the events leading to the malignant transformation of virally infected cells [9]. The E6 proteins are not long polypeptides, consisting of around 150 amino acids and have two Zinc- Finger domains E6C and E6N [10-13]. The E6C domain of HPV16 remains monomeric, while the E6N domain homodimerizes at high concentrations. Since E6 oncoproteins trigger p53 degradation, which is associated with tumor progression. Hence E6 has been suggested as the best possible cancer therapeutic agent [14]. The HPV viral infection degrades the activation of tumor suppressor protein p53 [15]. HPV oncoproteins such as E6 act by binding to p53 protein, as a result triggering degradation via proteasomes [8].
The intracellular accretion of the two oncoproteins, E6 and E7, is a significant molecular determinant of HPV-induced keratinocyte transformation [16]. Notably, the E6 plays a vital part in cancer growth and progression because of its significant inhibition effects on numerous onco suppressor signalling pathways such as P53 pathway. E6 not have enzymatic activity and relies primarily on protein-protein interactions (PPIs) to carry out its tasks [17].
The
