Molecular docking analysis of a secondary metabolite with the glycoprotein receptors of HSV 1 and HSV 2

Herpes simplex viruses (HSV) are alpha herpes viruses, which causes life-threatening illness. Therefore, it is of interest to design and develop potential drugs to treat HSV infections. We show the optimal molecular docking properties of a secondary metabolite (3, 7, 11, 15 tetra methyl-2-2-hexadecen-'1-ol) with the glycoprotein receptors of HSV1 and HSV 2 for further consideration.


Background:
Herpes simplex virus 1 and 2 are classified in the family of an alpha herpes virus, which causes mucal lesions in the oral and reproductive organs. Globally 1.6 million new cases of HSV were reported every year, where 22% of adults in USA show antibody for the virus [1, 2]. Both HSV 1 and 2 are highly contagious pathogens causing recurrent lesions. Herpes infections are caused by entry in to cells to trigger the envelope film or cell-cell combination [3]. There are four major viral envelope glycoproteins gD, gE, gB, and gH which help in inducing infection in the host by entry and replication in the cells. Glycoprotein D (gD) is the receptor protein which binds activates the other heterodimer such as gH/gL to elicit gB to mediate the fusion of viral and host cellular membranes. Virus entries [4] lead cause recurrent lesions. Therefore, the glycoproteins are key molecular machinery with highly conserved common domains as target for the novel discovery of antiherpes drugs. Ethanolic, chloroform and aqueous extracts of Justicae adothoda leaves were evaluated for the antiviral activity. Among the extracts, the ethanolic extract of Justicae adothoda revealed a promising antiviral activity. Further, the extracts were identified through analytical techniques such as gas chromatography, mass spectra and high-pressure thin layer chromatography. The GCMS chromatogram of ethanolic extract depicts the presence of active compound Phytal.
Phytal is a naturally occurring organic compound belonging to the member of diterpenoids. It is a long chain unsaturated acyclic alcohols, which exhibits wide range of biological activities. It is used as aroma compound with prospective candidate for a wide range of applications in the chemotherapeutics and other biotechnological industry. Phytal exerts many medicinal properties such as antimicrobial, anti-inflammatory, anti nociceptive, anxiolytic, immuno modulating, metabolism modulating, antioxidant, autophagy, and apoptosis inducing activity and 888 ©Biomedical Informatics (2019) cytotoxicity effects. Therefore, it is of interest to design and develop potential drugs to treat HSV infections. We show the optimal molecular docking properties of a secondary metabolite (3,7,11,15 tetra methyl-2-2-hexadecen-'1-ol) with the glycoprotein receptors of HSV1 and HSV 2 for further consideration.

Methodology: Preparation and optimization of receptors and ligands:
The 3-dimensional glycoprotein-D, E structures of HSV 1 & 2 were downloaded from the protein data bank (PDB) Research Collaboration for Structural Biology (RCSB) [5] files with PDB IDs 2C36, 3U82, 2GIY and 4MYV). It was optimized using Discovery Studio and then exported into docking tools (MT, Ligplot and Autodock). The receptor protein was analysed using side chain packing, energy minimization and optimization using protein preparation tools. The hydrogen atoms were added, bond orders were assigned and waters molecules were removed from the exterior to 5Å site. The P ionization, optimization, energy minimization was done for the 3D geometry of targeted receptors. The ligands were prepared using ligplot and docking was done using Auto dock. 3-D structures of the ligands were optimized as described else were Banks et al. [6].
The molecular docking framework for HSV-1 protein (PDB: 2KI5) shown was created using Autodock as described elsewhere [7]. Discovery studio was used for visualization of the glycoproteins of HSV 1 and 2 proteins with data corresponding to PDB ID: 2C36, 3U82, 2GIY and 4MYV. The ligand was optimized using ligplot. The van der Waals (vdW) scaling factor fractional incriment was selected as 0.85, 0.25, respectively for ligand atoms. The docking scores were calculated using atomic contact energy, energy transformation and score values [8]. ADME properties of the phytal ligand were calculated using PreADMET/Tox tools [9]. The parameters such as SK logS-pure, SK logS-buffer, SK log P-value and SK logD-value for Cytochrome P450 families CYP-3A4substrate, CYP-3A4-inhibition, CYP-2D6-substrate, CYP-2D6inhibition, CYP-2C9-inhibition and CYP-2C19-inhibition, Plasma protein binding, Blood brain wall penetration, Skin permeability, human intestinal absorption, Cellular permeability by Caco2 and cell lines (MDCK) were calculated using PreADMET/Tox tools.

Molecular properties and drug likeliness prediction:
Molecular properties and drug likeliness were calculated using molinspiration (https://www.molinspiration.com/). This tool predicts the parameters such as LogP, Total Polar surface Area (TPSA), molecular volume and Rule 5 properties [9]. The log pvalue is calculated on the basis of contribution by octanol/water coefficient. TPSA is the sub-atomic polar surface region description of the compound. This parameter determines the drug absorption in intestine, bioavailability, permeability and penetration. The number of rotatable bonds reflects the oral bioavailability of drugs based on the lone pair non-ring bond with non-terminal heavy atoms. The TPSA is calculated as described elsewhere [10]. Drug likeliness of compounds was assessed using the prediction tool Molinspiration.

Rule of 5 properties:
Atomic descriptors used in Lipinski "Standard Rule of 5 properties" were described elsewhere [2]. It states that most "tranquilize like" particles have logP <= 5, sub-atomic weight <= 500, number of hydrogen bond acceptors <= 10, and number of hydrogen bond contributors <= 5. Atoms disregarding more than one of these guidelines may have issues with bioavailability. The standard is classified as "Rule of 5".

Number of rotatable bonds (nrotb):
This topological parameter is related to sub-atomic adaptability. It is a descriptor of oral bioavailability of drug like compounds [3]. Rotatable bond is characterized as a single non-ring bond that is limited to non-terminal overwhelming (i.e., non-hydrogen) molecule. Amide C-N bonds are not considered in light of their high rotational vitality barrier.

Results:
The binding of the compound phytal (3,7,11,15 tetra methyl-2-2hexadecen-`1-ol) with the glycoprotein envelope proteins D and E of HSV 1 and 2 is studied in this analysis with ADMET evaluations. Data on the active compounds of Justicia adathoda were known available from Gas chromatography and Mass spectroscopy analysis. The ligand structure is generated using ligplot (Figure 1). The crystal structures of receptors (Figure 2) were optimized using Discovery studio and their binding pockets were identified using molecular tools supported by supercomputing facilities. The docking between phytal and the HSV 1 and 2 glycoprotein receptors gD and gE were completed using AutoDock as shown in Figure 3 and Figure 4 with molecular binding features summarized in Table 1, Table 2 and Table 3. The ADMET properties of the protein-ligand complex are given in Table 4 and Figure 5.

Discussion:
Glycoproteins are the key molecular targets of HSV. There are 11 glycoproteins on the HSV lipid membrane. It is known that 5 among them 5 are linked with cell entry: gB, gC, gD, and the heterodimer gH/gL  Three classes of receptors for HSV gD have been depicted. HveA (herpesvirus entry mediator A also called HVEM and TNFRSF14) is a member of the tumor necrosis factor receptor superfamily [11]. It is expressed on activated lymphocytes where it intercedes HSV entry [12]. The cellular function of HveA is to bind the TNF-like ligands. It has been reported that HSV-infected cytotoxic lymphocytes (CTL) rapidly eliminates to other T cells ("fratricide") and speculated that infection of activated CTLs might provide the virus with a mechanism to evade host immunity. The class-II receptors including HveC immunoglobulin (Ig) also termed as nectin-1 superfamily members with one V-like and two C-like Ig domains. These proteins are functioned as homophilic adhesion molecules on the surface of neuronal and epithelial cells. gD of HSV-1 is a glycoprotein with 369 residues with an N-terminal ectodomain of 316 residues having three N-linked oligosaccharide attachment sites. The receptor has six cysteines residues, which forms 3 disulfide bonds between Cys 66-189, Cys 106-202, and Cys 118-127. Ectodomains of gD truncated residues 285 (gD285) or 275 (gD275) inhibits infection and bind to receptors in vitro 100 times better than a longer form gD306. Hence, we describe the optimal molecular docking properties of a secondary metabolite (3, 7, 11, 15 tetra methyl-2-2-hexadecen-'1-ol) with the glycoprotein receptors of HSV1 and HSV 2 for further consideration. Glycoprotein D is encoded by the gene US6 and in plays a chief role in antigenic determinant in the HSV-1 viral envelope. The glycoprotein D in the HSV-1 viral envelop undergo frequent mutation for adherence of viral host cell interaction. The mutation in the glycoprotein D (glD) is unable to penetrate the host cell membrane for the establishment of infection in the host.