Unraveling the multi-targeted curative potential of bioactive molecules against cervical cancer through integrated omics and systems pharmacology approach.

Molecular level understanding on the role of viral infections causing cervical cancer is highly essential for therapeutic development. In these instances, systems pharmacology along with multi omics approach helps in unraveling the multi-targeted mechanisms of novel biologically active compounds to combat cervical cancer. The immuno-transcriptomic dataset of healthy and infected cervical cancer patients was retrieved from the array express. Further, the phytocompounds from medicinal plants were collected from the literature. Network Analyst 3.0 has been used to identify the immune genes around 384 which are differentially expressed and responsible for cervical cancer. Among the 87 compounds reported in plants for treating cervical cancer, only 79 compounds were targeting the identified immune genes of cervical cancer. The significant genes responsible for the domination in cervical cancer are identified in this study. The virogenomic signatures observed from cervical cancer caused by E7 oncoproteins serve as the potential therapeutic targets whereas, the identified compounds can act as anti-HPV drug deliveries. In future, the exploratory rationale of the acquired results will be useful in optimizing small molecules which can be a viable drug candidate.

Structural Understanding of SARS-CoV-2 Drug Targets, Active Site Contour Map Analysis and COVID-19 Therapeutics.

The pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV- 2), is responsible for multiple worldwide lockdowns, an economic crisis, and a substantial increase in hospitalizations for viral pneumonia along with respiratory failure and multiorgan dysfunctions. Recently, the first few vaccines were approved by World Health Organization (WHO) and can eventually save millions of lives. Even though, few drugs are used in emergency like Remdesivir and several other repurposed drugs, still there is no approved drug for COVID-19. The coronaviral encoded proteins involved in host-cell entry, replication, and host-cell invading mechanism are potential therapeutic targets. This perspective review provides the molecular overview of SARS-CoV-2 life cycle for summarizing potential drug targets, structural insights, active site contour map analyses of those selected SARS-CoV-2 protein targets for drug discovery, immunology, and pathogenesis.

Structural dynamic studies on identification of EGCG analogues for the inhibition of Human Papillomavirus E7.

High risk human papillomaviruses are highly associated with the cervical carcinoma and the other genital tumors. Development of cervical cancer passes through the multistep process initiated from benign cyst to increasingly severe premalignant dysplastic lesions in an epithelium. Replication of this virus occurs in the fatal differentiating epithelium and involves in the activation of cellular DNA replication proteins. The oncoprotein E7 of human papillomavirus expressed in the lower epithelial layers constrains the cells into S-phase constructing an environment favorable for genome replication and cell proliferation. To date, no suitable drug molecules exist to treat HPV infection whereas anticipation of novel anti-HPV chemotherapies with distinctive mode of actions and identification of potential drugs are crucial to a greater extent. Hence, our present study focused on identification of compounds analogue to EGCG, a green tea molecule which is considered to be safe to use for mammalian systems towards treatment of cancer. A three dimensional similarity search on the small molecule library from natural product database using EGCG identified 11 potential small molecules based on their structural similarity. The docking strategies were implemented with acquired small molecules and identification of the key interactions between protein and compounds were carried out through binding free energy calculations. The conformational changes between the apoprotein and complexes were analyzed through simulation performed thrice demonstrating the dynamical and structural effects of the protein induced by the compounds signifying the domination. The analysis of the conformational stability provoked us to describe the features of the best identified small molecules through electronic structure calculations. Overall, our study provides the basis for structural insights of the identified potential identified small molecules and EGCG. Hence, the identified analogue of EGCG can be potent inhibitors against the HPV 16 E7 oncoprotein.

Computational identification and antifungal bioassay reveals phytosterols as potential inhibitor of Alternaria arborescens.

Alternaria arborescens is a major pathogen for crops like tomato, tangerine and so on and its control is mostly dependent on the application of chemical agents. Plants as the sources of natural products are very attractive option for developing eco-friendly and natural antifungal agents. In this study, we modeled three-dimensional structure of chorismate synthase (CS) enzyme from A. arborescens. Docking studies of phytosterols, namely, γ-sitosterol and ß-sitosterol, with CS showed them to be potential inhibitor of CS. To explore the stability and conformational flexibility of all the AaCS complex systems, molecular dynamics simulations were performed. None of the putative inhibitors as well as ß- and γ-sitosterol showed interaction with the FMNH2 binding pocket of the tomato CS (major host of A. arborescens) indicating their suitability as antifungal compounds inhibiting the shikimate pathway without causing any harm to the host. An in vivo antifungal bioassay showed a significant reduction in fungal growth in the presence of ß-sitosterol (500 ppm) which resulted in ∼23% and ∼17% reduction in fungal fresh and dry weight, respectively, at 8 days after inoculation. This study provides experimental evidence establishing natural sterols like ß-sitosterol can be useful in curbing A. arborescens damage in an eco-friendly manner.Communicated by Ramaswamy H. Sarma.

Discovery of Potent Inhibitors for the Inhibition of Dengue Envelope Protein: An In Silico Approach.

BACKGROUND: Dengue fever, a major public health problem in the tropical and sub-tropical countries caused by the infection of Dengue virus transmitted by the anthropod vectors. The dengue virus infection is represented as the "Neglected Tropical Diseases" by the world health organization. The structural protein E binds to the receptor on the host cell surface during infection and the binding directs to the endocytic pathway. The conformational change of the envelope protein helps to infuse the viral lipid membrane and delivers the viral genome into the cytosol. No specific treatments are available till date and development of the vaccine for the DENV is challenging due to the immunization and longlasting protection against all four serotypes. Hence, identification of potent inhibitors would overlay the therapeutics against the mediated diseases. OBJECTIVE: Our study focuses on developing the novel potent inhibitors to inhibit the viral attachment and membrane fusion of the Dengue virus Envelope protein. METHODS: The crystal structure of Dengue Envelope protein has been retrieved from the protein data bank and optimized through Schrödinger. The structure-based virtual screening based on the cocrystallised ligand has been carried out with the small molecule libraries, and based on the docking score, interaction and energy value best complexes were selected. The selected complexes were further taken forward for the conformational stability analysis through Molecular dynamics simulation. RESULTS: Around 55 molecules from the three databases were identified as potential binders to the envelope protein and the docking studies revealed that the top compounds possess strong interaction with the good energies. The Molecular electrostatic surface potential of the top five compounds states that the interactions were observed mostly in the electropositive region. Finally, the best 5 compounds carried further for molecular dynamics simulations exposed that they were highly stable and no loss of interactions was observed between those complexes. CONCLUSION: Hence, from the results, it is evident that the compounds DB00179, Quercetin, Silymarin, Dapagliflozlin and Fisetin could be novel and potent candidates to inhibit the DENV envelope protein.

E7 oncoprotein of human papillomavirus: Structural dynamics and inhibitor screening study.

Human papillomavirus (HPV) has been the primary causative agent of cervical cancer, the most threatening cancer affecting millions of women worldwide. HPV, a small non enveloped DNA virus of high and low risk types contain intrinsically disordered region and it also plays significant role in the development of cervical cancer. HPV E7 contains an ordered Zinc finger motif that binds to pRB and alters its function. It utilizes both disordered N-terminal and structured C-terminal regions for cellular transformation. In this study, we have focused extensively on the evolutionary relationships of E7 among various HPV types and generated a 3D homology model of full length HPV 16 E7, since the structure have not been solved till date. We also analysed the stable conformation and atomic flexibility of modelled E7 through molecular dynamics simulation at 100 ns. To understand the disordered based binding sites of E7 oncoprotein, Molecular recognition features (MoRFs) analysis was carried out on the E7 oncoprotein. The validated model was taken forward for the identification of potential lead compounds and the most prominent compounds were selected for the molecular dynamics simulation of the 100 ns for the stability analysis. Overall, this study highlights the holistic E7 regions including important disordered based binding sites analysed through the MoRFs. The potential inhibitor compound that targets the structured C-terminal region of E7 oncoprotein were subjected for the pharmacological properties analysis and further validated for the binding modes of the compounds with the target structure. This study helps in providing a better intuition to develop a potent anti-HPV agent.