Molecular modeling simulation studies reveal new potential inhibitors against HPV E6 protein

Ricci-Lopez, Joel; Vidal-Limón, Abraham; Zunñiga, Matías; Jiménez, Verónica A.; Alderete, Joel B.; Brizuela, Carlos A.

doi:10.1371/journal.pone.0213028

Cited by 36 publications

(23 citation statements)

References 58 publications

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“…The application of ED to analyze protein behaviour mainly focuses on the dominant modes of motion, which are obtained by decomposing the covariance matrix and by ranking the eigenvectors (principal components) in descending order of the corresponding eigenvalues [292,332]. By plotting the first two or three principal components against each other, we obtain a general idea of the distribution for all generated conformations obtained from a conformational sampling experiment, as exemplified from ED analyzes for various proteins [333][334][335][336]. On the resulting figure, one may obtain conformationally distinct clusters of the simulated proteins or complexes.…”

Section: Essential Dynamics and Free-energy Landscapementioning

confidence: 99%

Integrated Computational Approaches and Tools for Allosteric Drug Discovery

Amamuddy

Veldman

Manyumwa

et al. 2020

IJMS

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Understanding molecular mechanisms underlying the complexity of allosteric regulation in proteins has attracted considerable attention in drug discovery due to the benefits and versatility of allosteric modulators in providing desirable selectivity against protein targets while minimizing toxicity and other side effects. The proliferation of novel computational approaches for predicting ligand–protein interactions and binding using dynamic and network-centric perspectives has led to new insights into allosteric mechanisms and facilitated computer-based discovery of allosteric drugs. Although no absolute method of experimental and in silico allosteric drug/site discovery exists, current methods are still being improved. As such, the critical analysis and integration of established approaches into robust, reproducible, and customizable computational pipelines with experimental feedback could make allosteric drug discovery more efficient and reliable. In this article, we review computational approaches for allosteric drug discovery and discuss how these tools can be utilized to develop consensus workflows for in silico identification of allosteric sites and modulators with some applications to pathogen resistance and precision medicine. The emerging realization that allosteric modulators can exploit distinct regulatory mechanisms and can provide access to targeted modulation of protein activities could open opportunities for probing biological processes and in silico design of drug combinations with improved therapeutic indices and a broad range of activities.

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Section: Essential Dynamics and Free-energy Landscapementioning

confidence: 99%

Integrated Computational Approaches and Tools for Allosteric Drug Discovery

Amamuddy

Veldman

Manyumwa

et al. 2020

IJMS

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“…Using 26 reference compounds, mostly flavonoids, known to inhibit E6, this group created a large compound library based on structural similarity to the references, and then utilized docking screening and molecular dynamic simulations to virtually screen and validate the hits. They identified three novel compounds, lig1, 2, and 3 [ 65 ]. However, follow-up experiments to validate p53 rescue or apoptosis induction in HPV + cells are still pending.…”

Section: Therapeutic Targeting Of E6 Ppismentioning

confidence: 99%

PPI Modulators of E6 as Potential Targeted Therapeutics for Cervical Cancer: Progress and Challenges in Targeting E6

Chitsike

Duerksen-Hughes

2021

Molecules

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Advanced cervical cancer is primarily managed using cytotoxic therapies, despite evidence of limited efficacy and known toxicity. There is a current lack of alternative therapeutics to treat the disease more effectively. As such, there have been more research endeavors to develop targeted therapies directed at oncogenic host cellular targets over the past 4 decades, but thus far, only marginal gains in survival have been realized. The E6 oncoprotein, a protein of human papillomavirus origin that functionally inactivates various cellular antitumor proteins through protein–protein interactions (PPIs), represents an alternative target and intriguing opportunity to identify novel and potentially effective therapies to treat cervical cancer. Published research has reported a number of peptide and small-molecule modulators targeting the PPIs of E6 in various cell-based models. However, the reported compounds have rarely been well characterized in animal or human subjects. This indicates that while notable progress has been made in targeting E6, more extensive research is needed to accelerate the optimization of leads. In this review, we summarize the current knowledge and understanding of specific E6 PPI inhibition, the progress and challenges being faced, and potential approaches that can be utilized to identify novel and potent PPI inhibitors for cervical cancer treatment.

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“…Flavanoid compounds, Luteolin and CAF024, which mimic leucines in the conserved alpha helical motif of E6AP have been found to inhibit the E6–E6AP interaction [ 134 ]. Molecular modelling and simulation studies have revealed some additional inhibitors of the E6–E6AP interaction [ 135 ]. It has been demonstrated that the space between the two Zinc finger domains of E6 constitutes the LxxLL binding pocket [ 136 ].…”

Section: Therapeutic Approaches To Target E6ap and Downstream Effementioning

confidence: 99%

The HECT E3 Ligase E6AP/UBE3A as a Therapeutic Target in Cancer and Neurological Disorders

Owais

Mishra

Kiyokawa

2020

Cancers

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The HECT (Homologous to the E6-AP Carboxyl Terminus)-family protein E6AP (E6-associated protein), encoded by the UBE3A gene, is a multifaceted ubiquitin ligase that controls diverse signaling pathways involved in cancer and neurological disorders. The oncogenic role of E6AP in papillomavirus-induced cancers is well known, with its action to trigger p53 degradation in complex with the E6 viral oncoprotein. However, the roles of E6AP in non-viral cancers remain poorly defined. It is well established that loss-of-function alterations of the UBE3A gene cause Angelman syndrome, a severe neurodevelopmental disorder with autosomal dominant inheritance modified by genomic imprinting on chromosome 15q. Moreover, excess dosage of the UBE3A gene markedly increases the penetrance of autism spectrum disorders, suggesting that the expression level of UBE3A must be regulated tightly within a physiologically tolerated range during brain development. In this review, current the knowledge about the substrates of E6AP-mediated ubiquitination and their functions in cancer and neurological disorders is discussed, alongside with the ongoing efforts to pharmacologically modulate this ubiquitin ligase as a promising therapeutic target.

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Molecular modeling simulation studies reveal new potential inhibitors against HPV E6 protein

Cited by 36 publications

References 58 publications

Integrated Computational Approaches and Tools for Allosteric Drug Discovery

Integrated Computational Approaches and Tools for Allosteric Drug Discovery

PPI Modulators of E6 as Potential Targeted Therapeutics for Cervical Cancer: Progress and Challenges in Targeting E6

The HECT E3 Ligase E6AP/UBE3A as a Therapeutic Target in Cancer and Neurological Disorders

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