In Silico Approaches: A Way to Unveil Novel Therapeutic Drugs for Cervical Cancer Management

Abstract

Cervical cancer (CC) is the fourth most common pathology in women worldwide and presents a high impact in developing countries due to limited financial resources as well as difficulties in monitoring and access to health services. Human papillomavirus (HPV) is the leading cause of CC, and despite the approval of prophylactic vaccines, there is no effective treatment for patients with pre-existing infections or HPV-induced carcinomas. High-risk (HR) HPV E6 and E7 oncoproteins are considered biomarkers in CC progression. Since the E6 structure was resolved, it has been one of the most studied targets to develop novel and specific therapeutics to treat/manage CC. Therefore, several small molecules (plant-derived or synthetic compounds) have been reported as blockers/inhibitors of E6 oncoprotein action, and computational-aided methods have been of high relevance in their discovery and development. In silico approaches have become a powerful tool for reducing the time and cost of the drug development process. Thus, this review will depict small molecules that are already being explored as HR HPV E6 protein blockers and in silico approaches to the design of novel therapeutics for managing CC. Besides, future perspectives in CC therapy will be briefly discussed.

Keywords: E6 inhibitors; cervical cancer management; computer-aided drug design; human papillomavirus; in silico studies.

Figure 1

A map of different binding sites of the HPV16 E6 protein using PDB ID 4XR8 and 2KPL on Chimera software. Surface representation of E6 residues that participate in the binding with E6AP (A), p53 (B), and the PDZ domain (C). A—Orange residues participate in E6AP binding; B—The three interfaces of contact between E6 and p53 are colored in light, medium, and dark blue. C—The C-terminal PDZ binding motif is represented in green. E6N: N-terminal; E6C: C-terminal.

Figure 2

Structures of studied synthetic compounds as E6/E6AP inhibitors. IUPAC name of compounds—compound 1: (S)-N-((3-amino-1-(5-ethyl-7H-pyrrolo [2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-2,4-difluorobenzamide; compound 2: N-((6-methyl-1H-benzo[d]imidazol-2-yl)methyl)-5-(thiophen-2-yl)-1H-pyrazole-3-carboxamide; compound 3: N¹-(5-chloro-2-cyanophenyl)-N²-(2-hydroxy-2-(1-methyl-1H-indol-3-yl)ethyl)oxalamide; compound 4: (E)-6-((2S,3S)-2-((E)-5-((tert-butyldimethylsilyl)oxy)-2-methylpent-1-en-1-yl)-5-methoxytetrahydrofuran-3-yl)-4-methylhex-3-en-1-ol; compound 5: tert-butyl(((E)-5-((2S,3S)-5-methoxy-3-((E)-3-methylhexa-3,5-dien-1-yl)tetrahydrofuran-2-yl)-4-methylpent-4-en-1-yl)oxy)dimethylsilane; compound 6: 2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-8-methyl-4H-chromen-4-one; compound 7: (S)-(R)-2-((2-amino-6-oxo-1H-purin-9(6H)-yl)methoxy)-3-hydroxypropyl 2-amino-3-methylbutanoate; compound 8: 4-amino-1-((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one; compound 9: (R)-2-((2-amino-6-oxo-1H-purin-9(6H)-yl)methoxy)-3-hydroxypropyl 4-aminobenzoate.

Figure 3

Structures of studied synthetic compounds as E6/E6AP inhibitors acting by ejecting zinc ions. IUPAC name of compounds—compound 10: (E)-N¹-(2-amino-2-methylpropyl)-N¹-(thiophen-2-yl)diazene-1,2-dicarboxamide; compound 11: (E)-N¹-(2-amino-2-oxoethyl)-N¹-(4-chlorophenyl)diazene-1,2-dicarboxamide.

Figure 4

Structures of the studied natural compounds as E6/E6AP inhibitors. IUPAC name of compounds—compound 12: 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one; compound 13: 1’,5-dihydroxy-3’,7-dimethyl-[2,2’-binaphthalene]-1,4,5’,8’-tetraone; compound 14: (S)-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-one; compound 15: (S)-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-one; compound 16: ((2R,3R,4S,5R,6S)-4-hydroxy-3-(((2S,3R,4S,5R,6R)-5-hydroxy-6-(hydroxymethyl)-4-methyl-3-(sulfooxy)tetrahydro-2H-pyran-2-yl)oxy)-6-methoxy-5-(sulfooxy)tetrahydro-2H-pyran-2-yl)methyl hydrogen sulfate.

Figure 5

Structures of the studied natural compounds as E6/p53 inhibitors. IUPAC name of compounds—compound 17: (4S,4aR,5aR,6aS,6bS,9R,9aS,11aS,11bR)-4-hydroxy-9-((S)-1-((R)-5-(hydroxymethyl)-4-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-9a,11b-dimethyl-5a,6,6a,6b,7,8,9,9a,10,11,11a,11b-dodecahydrocyclopenta[1,2]phenanthro[8a,9-b]oxiren-1(4H)-one; compound 18: (2S,3R,4S,5S,6R)-2-(4-((2S,6R)-6-(3,4-dimethoxyphenyl)hexahydrofuro[3,4-b]furan-2-yl)-2-methoxyphenoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; compound 19: 7-hydroxy-6-methoxy-3-((2-oxo-2H-chromen-7-yl)oxy)-2H-chromen-2-one; compound 20: 5,7-dihydroxy-8-(5-(5-hydroxy-7-methoxy-4-oxo-4H-chromen-2-yl)-2-methoxyphenyl)-2-(4-hydroxyphenyl)-4H-chromen-4-one.

Figure 6

Structures of the studied synthetic compounds as E6/p53 inhibitors. IUPAC name of compounds—compound 21: 2-((4-fluorophenyl)amino)-6-(((1-phenyl-1H-tetrazol-5-yl)thio)methyl)pyrimidin-4(3H)-one; compound 22: N-(4-(benzo[d]thiazol-2-yl)phenyl)-5-chloro-2-methoxybenzamide.