Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Apr 29;14(5):940.
doi: 10.3390/v14050940.

Molecular Characterization and Identification of Potential Inhibitors for 'E' Protein of Dengue Virus

Rishi Gowtham Racherla  1 , Sudheer Kumar Katari  2 , Alladi Mohan  3 , Umamaheswari Amineni  2 , Manohar Badur  4 , Abhijit Chaudhury  5 , Mudhigeti Nagaraja  1 , Sireesha Kodavala  6 , Meenakshi Kante  1 , Usha Kalawat  1
Affiliations

Molecular Characterization and Identification of Potential Inhibitors for 'E' Protein of Dengue Virus

Rishi Gowtham Racherla et al. Viruses. .

Abstract

Dengue is an arthropod-borne acute febrile illness caused by Dengue Virus (DENV), a member of Flaviviridae. Severity of the infection ranges from mild self-limiting illness to severe life-threatening hemorrhagic fever (DHF) and dengue shock syndrome (DSS). To date, there is no specific antiviral therapy established to treat the infection. The current study reports the epidemiology of DENV infections and potential inhibitors of DENV 'E' protein. Among the various serotypes, DENV-2 serotype was observed more frequently, followed by DENV-4, DENV-1, and DENV-3. New variants of existing genotypes were observed in DENV-1, 2, and 4 serotypes. Predominantly, the severe form of dengue was attributable to DENV-2 infections, and the incidence was more common in males and pediatric populations. Both the incidence and the disease severity were more common among the residents of non-urban environments. Due to the predominantly self-limiting nature of primary dengue infection and folk medicine practices of non-urban populations, we observed a greater number of secondary dengue cases than primary dengue cases. Hemorrhagic manifestations were more in secondary dengue in particularly in the pediatric group. Through different computational methods, ligands RGBLD1, RGBLD2, RGBLD3, and RGBLD4 are proposed as potential inhibitors in silico against DENV-1, -2, -3, and -4 serotypes.

Keywords: dengue virus; envelope protein inhibitors; genotypes and serotypes; molecular dynamics simulation.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Trends of occurrence of different Dengue virus serotypes and their co-infections in the given geographic location during January 2017 to December 2017. Dengue cases were occurring throughout the year, with seasonal peaks in July and October months. During outbreaks all four dengue serotypes were observed with DENV-2 predominance. There were no hotspot regions observed during the study period in this (Raayalaseema region, Andhra Pradesh, India) part of the state.
Figure 2
Figure 2
Structure validation of DENV-1 by various in silico methods. (A) PROCHECK analysis (Ramachandran plot of the best DENV-1 model). (B) Model quality before minimization (ProSA). (C) Model quality after minimization (ProSA). (D) Per residue model quality before minimization. (E) Per residue model quality after minimization. (F) Ribbon form of DENV-1 structure before minimization (blue color—least energy regions; red color—highest energy regions). (G) Ribbon form of DENV-1 structure after minimization (blue color—least energy regions; red color—highest energy regions). Structure of DENV-1 envelop protein and docking and dynamics interactions of reference and novel inhibitor molecules. (H) Cartoon representation of the best DENV-1 dimer model (A chain in green color and B chain in cyan color). (I) Best docked published inhibitor (Agnuside) interactions with DENV-1. (J) Best docked lead 1 (RGBLD-1) interactions with DENV-1; RGBLD1 showed interactions with 17 amino acids. Six bonded interactions (Hydrogen-5, Salt bridge-1) were found. Glu85, Asn232, Gln234, Asp235, Cys92 showed hydrogen bonding with RGBLD1; Lys79 showed salt bridge interaction. Non-bonding interactions include polar, hydrophobic, positive charge, and negative charge with amino acids Ala88, Phe90, Val91, Leu114, Arg94, Arg93 of chain A and Asn727, Cys726, Thr725, Ala583 of chain B of DENV-1. (K) DENV-1-RGBLD-1 (protein ligand contacts) in 100 ns molecular dynamics simulations.
Figure 3
Figure 3
Structure validation of DENV-2 by various in silico methods. (A) PROCHECK analysis (Ramachandran plot of the best DENV-2 model). (B) Model quality before minimization (ProSA). (C) Model quality after minimization (ProSA). (D) Per residue model quality before minimization. (E) Per residue model quality after minimization. (F) Ribbon form of DENV-2 structure before minimization (blue color—least energy regions; red color—highest energy regions). (G) Ribbon form of DENV-2 structure after minimization (blue color—least energy regions; red color—highest energy regions). Structure of DENV-2 envelop protein and docking and dynamics interactions of reference and novel inhibitor molecules. (H) Cartoon representation of the best DENV-2 dimer model (A chain in blue color and B chain in yellow color). (I) Best docked published inhibitor (Rhodiolin) interactions with DENV-2. (J) Best docked lead 1 (RGBLD-2) interactions with DENV-2; In DENV-2, RGBLD2 showed interactions with 14 amino acids. Ten bonded interactions were found consisting of hydrogen bonding with Arg288, Arg286, Arg20 in chain A; Leu342, Glu343, Gln386, Arg345 in chain B. Pi–pi stacking was observed in Arg288 in chain A, Tyr377 in chain B. Salt bridge with Arg20 was observed in chain A. Non-bonding interactions include polar, hydrophobic, positive charge, and negative charge with amino acids Phe186, Phe169 of chain A; Lys344, Met340, Ile379, Lys388 of chain B in DENV-2. (K) DENV-2-RGBLD-2 (protein ligand contacts) in 100 ns molecular dynamics simulations.
Figure 4
Figure 4
Structure validation of DENV-3 by various in silico methods. (A) PROCHECK analysis (Ramachandran plot of the best DENV-3 model). (B) Model quality before minimization (ProSA). (C) Model quality after minimization (ProSA). (D) Per residue model quality before minimization. (E) Per residue model quality after minimization (F) Ribbon form of DENV-3 structure before minimization (blue color—least energy regions; red color—highest energy regions). (G) Ribbon form of DENV-3 structure after minimization (blue color—least energy regions; red color—highest energy regions). Structure of DENV-3 envelope protein and docking and dynamics interactions of reference and novel inhibitor molecules. (H) Cartoon representation of the best DENV-3 dimer model (A chain in magenta color and B chain in red color). (I) Best docked published inhibitor (Chlorogenic acid) interactions with DENV-3. (J) Best docked lead 1 (RGBLD-3) interactions with DENV-3; In DENV-3, RGBLD3 showed interactions with 13 amino acids. Five bonded interactions were found comprising of hydrogen bonding with Lys232 of chain A; His92, Lys91, Cys90 of chain B. Salt bridge was observed in Lys91 of chain B. Non-bonding interactions include polar, hydrophobic, positive charge, and negative charge with amino acids Leu88, Trp229, Glu233, Leu91, Arg231, Asn230 of chain A; Leu89, Glu231 of chain B. (K) DENV-3-RGBLD-3 (protein ligand contacts) in 100 ns molecular dynamics simulations.
Figure 5
Figure 5
Structure validation of DENV-4 by various in silico methods. (A) PROCHECK analysis (Ramachandran plot of the best DENV-4 model) (B) Model quality before minimization (ProSA) (C) Model quality after minimization (ProSA) (D) Per residue model quality before minimization. (E) Per residue model quality after minimization (F) Ribbon form of DENV-4 structure before minimization (blue color—least energy regions; red color—highest energy regions). (G) Ribbon form of DENV-4 structure after minimization (blue color—least energy regions; red color—highest energy regions). Structure of DENV-4 envelop protein and docking and dynamics interactions of reference and novel inhibitor molecules. (H) Cartoon representation of the best DENV-4 dimer model (A chain in silver color and B chain in brown color). (I) Best docked published inhibitor (NITD448) interactions with DENV-4. (J) Best docked lead 1 (RGBLD-4) interactions with DENV-4; In DENV-4, RGBLD4 showed interactions with 21 amino acids. Seven hydrogen bonding were found with Glu85, Gln86, Gln88, His230, His233, Asn232 of chain A; Glu85 of chain B. Non-bonding interactions include polar, hydrophobic and negative charge with amino acids Thr234, Trp231, Ile91, Gln89, Tyr90, Cys92 of chain A; His230, Gln89, Gln86, Tyr90, Asp87, Gln88, Ile91, Cys92 of chain B. (K) DENV-4-RGBLD-4 (protein ligand contacts) in 100 ns molecular dynamics simulations.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Racherla R.G., Pamireddy M.L., Mohan A., Mudhigeti N., Mahalakshmi P.A., Nallapireddy U., Kalawat U. Co-Circulation of Four Dengue Serotypes at South Eastern Andhra Pradesh, India: A Prospective Study. Indian J. Med. Microbiol. 2018;36:236–240. doi: 10.4103/ijmm.IJMM_18_109. - DOI - PubMed
    1. Gubler D.J. Epidemic dengue/dengue hemorrhagic fever as a public health, social and economic problem in the 21st century. Trends Microbiol. 2002;10:100–103. doi: 10.1016/S0966-842X(01)02288-0. - DOI - PubMed
    1. National Vector Borne Diseases Control Programme, New Delhi Clinical Management of Dengue Fever (DF) and Dengue Haemorrhagic Fever (DHF) [(accessed on 15 November 2021)];2008 Available online: http://www.nvbdcp.gov.in/Doc/Clinical%20Guidelines.pdf.
    1. Klungthong C., Gibbons R.V., Thaisomboonsuk B., Nisalak A., Kalayanarooj S., Thirawuth V., Nutkumhang N., Mammen M.P., Jr., Jarman R.G. Dengue Virus Detection Using Whole Blood for Reverse Transcriptase PCR and Virus Isolation. J. Clin. Microbiol. 2007;45:2480–2485. doi: 10.1128/JCM.00305-07. - DOI - PMC - PubMed
    1. Shukla M.K., Barde P.V., Singh N. Utility of CDC DENV 1–4 real-time RT-PCR assay for the diagnosis of dengue. Dengue. 2018;40:15.

Publication types

Grants and funding

This research was partially supported by the Sri Balaji Arogya Vara Prasadini Scheme (SBAVP) (SBAVP-RG/Ph.D./18), Sri Venkateswara Institute of Medical Sciences (SVIMS), University and Tirumala Tirupati Devastanams (TTD), Tirupati, India. The Indian Council of Medical Research (ICMR) provided the Senior Research Fellowship (SRF) (2017-1024/CMB-BMS) grant to the researchers.