Videoing B and its Stereoisomers as Inhibitors of Nipah Virus- An In-silico Study of Structure-Based Virtual Screening and Comparative ADMET Profiling

 Corresponding author: Shubhangi P Patil Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution License 4.0. Videoing B and its Stereoisomers as Inhibitors of Nipah VirusAn In-silico Study of Structure-Based Virtual Screening and Comparative ADMET Profiling Kulsoom Bano Z Sayed, Deepa N Rangadal and Shubhangi P Patil * Department of Chemistry, The Institute of Science, 15, Madam Cama Road, Mantra Laya, Fort, Mumbai, Maharashtra 400032, India. GSC Biological and Pharmaceutical Sciences, 2025, 33(01), 344-363 Publication history: Received on 06 September 2025; revised on 26 October 2025; accepted on 29 October 2025 Article DOI: https://doi.org/10.30574/gscbps.2025.33.1.0399 Abstract Nipah virus (NiV) can cause a pandemic. Since there are no effective treatments available for NiV, the development of drugs requires immediate attention. In the context of drug discovery, natural products have emerged as a promising branch with tremendous scope. In this study, we screened 959 phytochemicals from 10 Indian medicinal plants using the IMPPAT database, PyRx, ProTox 3.0, SwissADME and AutoDock 4. Videoin B (L2) bypassed all 7 screening levels. Its stereoisomeric forms (1R,2R,4aS,6S,8aS)-2,5,5,8a-tetramethyl-5'-oxo-octahydro-2H-spiro[naphthalene-1,2'-oxolan]-6yl acetate (L1) and (1S,2S,4aR,6R,8aR)-2,5,5,8a-tetramethyl-5'-oxo-octahydro-2H-spiro[naphthalene-1,2'-oxolan]-6-yl acetate (L3) were obtained from the LOTUS database. L1, L2 and L3 showed binding score of -6.7, -7.5 and -7.8 kcal/mol respectively, better than the standardRibavirin (L0) when docked with the attachment glycoprotein of NiV. The impact of stereoisomerism on inhibitory action, drug-like properties, ADMET profiles, and toxicology was thoroughly examined by using ADMETlab. Better docking scores, improved pharmacokinetics, medicinal properties, ADMET profiles and reduced toxicity concerns suggest that these three natural productsL1, L2 and L3 can be potent candidates for the novel drug discovery of Niv. Hence, this study is a step towards pandemic preparedness and aims to contribute to the drug development of deadly NiV. Keywords: Nipah Virus; In-Silico Analysis; Structure-Based Virtual Screening; Stereoisomers; Docking; ADMET GSC Biological and Pharmaceutical Sciences, 2025, 33(01), 344-363 345 Graphical Abstract 1. Introduction Nipah virus (NiV) belongs to genus henipavirus, family Paramyxoviridae and order Mononegaviruses (1–4). It is a highly pathogenic, zoonotic virus (5). It is enveloped, has negative-sense single-stranded RNA and is considered a pathogen corresponding to biosafety level 4, hence needing utmost care in laboratory handling (2,6,7). Pteropid fruit bats, also called as flying foxes, are primarily the natural reservoir of NiV (2,6,8–12). Their excreta and saliva help in transmitting the virus and causing disease to secondary hosts/intermediate hosts (domestic animals like pigs, goats, horses, etc.), which in turn spread infection in humans when consumed (5,13). Humans and animals can develop the disease by eating bat-bitten dates or other fruits. The viral envelope has the attachment G and fusion F protein responsible for its entry into the host cell (11,14). Broad-spectrum antivirals like Ribavirin, Remdesivir and Flavipiravir are used in the treatment of NiV (3,4,15). NiV infections lead to inflammation of the brain, causing encephalitis and eventually death (2,15). Since it has high death rates, researchers are in desperate search of an effective medication, for which natural products can turn out to be a good option. In the context of drug discovery, this branch has limited exploration and tremendous scope. Direct lab exploration is immensely time and resource-consuming; hence, in-silico approaches are used to bridge this gap and save time and resources. GSC Biological and Pharmaceutical Sciences, 2025, 33(01), 344-363 346 Figure 1 Global impact and percent mortality rate of Niv Countries in which NiV spread has been reported are Malaysia, Singapore, Philippines, India and Bangladesh (16–18). Global impact has been shown in Fig. 1, which gives the mortality rate from year 1998 to 2023 for each country. The first outbreak was in Malaysia in 1998 with a 40% mortality rate, followed by Singapore in 1999 with a mortality rate as low as 9%. Similarly, there was only one outbreak in Philippines in 2014. Bangladesh had the maximum number of cases with a considerably high fatality rate, almost every year. India comes second in the list, but the outbreak was not observed regularly, as seen in the case of Bangladesh. In 2021, India had a 100% mortality rate. In India, the first outbreak was in Siliguri City (West Bengal) in 2001 (1,6). There are 2 strains of this virusBangladeshi and Malaysian, the former being more virulent than the latter because it shows human-to-human transmission and is circulated in India due to close geographical proximity. This virus is currently restricted to certain regions, but it is capable of causing a pandemic (2). Natural products (NPs) and their derivatives show good results in clinical trials as effective drugs because they exhibit less toxicity as compared to synthetic drugs (19–21). Well-known anti-inflammatory drug acetylsalicylic acid, derived from Salix alba plant’s active component, is one of the most successful drugs marketed (22,23). Another such example is Colchicine from Colchicum autumnale, used for gout and various other inflammatory diseases (22,24). For COVID-19, Virofree was reported to fight SARS-CoV-2 infection (22). Furthermore, NPs used for COVID-19, like Myricetin (25,26), Punicalagin (26,27), Gallinamide A (26,28), have been reported. Few studied phytochemicals exhibiting Anti-HIV activity are Daphneodorins A & B (26,29), Kleinhospitine E (26,30), Beesioside (26,31). Anticancer agents have been developed by the U.S. National Cancer Institute with the help of NPs (32). Whereas Bifucatriol (26,33), Kakeromamide (26,34), Halymeniaol (26,35) are Anti-malarial agents obtained from plants. A few more reported compounds are Ubonodin (36), Santacruzamate A (26,37), Honaucin A (26,38,39). Automation can extensively and rapidly screen vast chemical libraries virtually against biological targets, speed up the drug discovery procedures (22,39–42). In the present research, we aim to identify potential inhibitors of the attachment-G protein of NiV by virtually screening 959 phytochemicals present in 10 Indian medicinal plants, namely Patala (Stereospermum suaveolens), Shalaparni (Desmodium gangeticum), Musta (Cyperus rotundus), Chirayata (Swertia chirata), Guduchi (Tinospora cordifolia), Bhunimba (Andrographis paniculata), Patha (Cissampelos pareira), Vasaka (Justicia adhatoda), Agnimantha (Clerodendrum phlomidis) and Nirgundi (Vitex negundo). Vitedoin B and its stereoisomeric forms- (1R,2R,4aS,6S,8aS)- 2,5,5,8a-tetramethyl-5'-oxo-octahydro-2H-spiro[naphthalene-1,2'-oxolan]-6-yl acetate and (1S,2S,4aR,6R,8aR)- 2,5,5,8a-tetramethyl-5'-oxo-octahydro-2H-spiro[naphthalene-1,2'-oxolan]-6-yl acetate were thoroughly studied to analyse the impact of stereoisomerism on inhibiting activity, binding affinity, pharmacokinetics, ADMET profiles and toxicology of all these NiV attachment glycoprotein-inhibiting molecules. GSC Biological and Pharmaceutical Sciences, 2025, 33(01), 344-363 347 2. Methods 2.1. Protein structure retrieval, quality assessment and structural validation. With careful consideration of various important parameters, the best structure of attachment glycoprotein of NiV came out to be 2VWD. The structure of the attachment glycoproteinG (2VWD) given in Fig. 2 was obtained from RCSB PDB (https://www.rcsb.org/) Protein Data Bank, which is a well-known database containing structures of different proteins in different forms (43–45). The structure was downloaded in PDB format, available amongst the various download options. The PDB DOI of the chosen protein is https://doi.org/10.2210/pdb2VWD/pdb. The 3D structure verification and quality assessment were done using the ERRAT score (46), Verify3D (https://www.doe-mbi.ucla.edu/verify3d/) (47) and Ramachandran plot from Discovery Studio Visualizer(48). Figure 2 3D structure of the attachment glycoprotein (PDB ID: 2VWD) of Niva 2.2. Standard & Ligands structure retrieval. Ribavirin, a broad-spectrum antiviral, was taken as the standard. Its structure was obtained from the PubChem database (https://PubChem.ncbi.nlm.nih.gov/) managed by the U.S National Institutes of Health (NIH) in SDF format, which was later converted to PDB and PDBQT format for docking. Structures of all phytochemicals present in 10 Indian medicinal plants were taken from the IMPPAT database (https://cb.imsc.res.in/imppat/). A similar structure search was done on PubChem. Stereoisomeric structures were obtained from the LOTUS database (https://lotus.naturalproducts.net/) (49). The molecular formula of all three ligands is C19H30O4. Table 1 enlists the PubChem ID/ LOTUS ID, canonical smiles and the structures of the standard and ligand. 2.3. Docking Initially, the protein preparation was done in UCSF ChimeraX 1.8 by removing all non-standard residues to remove the non-proteinous part and adding missing atoms, polar hydrogen and charges. Multiple docking for all phytochemicals with the druggable target (2VWD) was done in PyRx in 3 batches, having varied numbers of ligands. Later, L0, L1, L2 and L3 were docked with 2VWD in AutoDock 4 individually. After docking, binding affinities for the best binding pose of the ligand were tabulated in an Excel sheet. The output files generated contained the binding affinity of the top 9 poses, RMSD lower and upper bound and were saved as CSV files, which were further used for analysis. 2.4. ADMET Profiling Initially, ProTox 3.0 (https://tox.charite.de/protox3/) software was used to know the toxicity classes of the phytochemicals and SwissADME (http://www.swissadme.ch/) was used to check the ADME profiles of the phytochemicals during the screening stage. L1, L2 and L3 showed better binding scores and ADMET profiles than the standard-L0. hence, detailed ADMETabsorption, distribution, metabolism, excretion and toxicity profiling of L1, L2 and GSC Biological and Pharmaceutical Sciences, 2025, 33(01), 344-363 348 L3 was done in comparison with L0 with the help of ADMETlab (https://admetmesh.scbdd.com/). ADMETlab gave a detailed and complete analysis of all ADMET parameters(50). Table 1 Ligands, their structures, IDs and canonical smiles Ligand Canonical Smiles PubChem ID/ LOTUS ID Structures L0 Ribavirin (Standard) OC[C@H]1O[C@H]([C@@H] ([C@@H]1O)O) n1cnc(n1) C(=O) N 37542 L1 (1R,2R,4aS,6S,8aS)-2,5,5,8atetramethyl-5'-oxooctahydro-2Hspiro[naphthalene-1,2'- oxolan]-6-yl acetate CC(=O)O[C@H]1CC[C@@]2(C)[C @@H](CC[C@@H](C)[C@]23CC C(=O) O3) C1(C)C Q105025374 L2 2,5,5,8a-tetramethyl-5'-oxooctahydro-2Hspiro[naphthalene-1,2'- oxolan]-6-yl acetate CC(=O)OC1CCC2(C)C(CCC(C)C23 CCC(=O) O3)C1(C)C Q105025375 L3 (1S,2S,4aR,6R,8aR)-2,5,5,8atetramethyl-5'-oxooctahydro-2Hspiro[naphthalene-1,2'- oxolan]-6-yl acetate CC(=O)O[C@@H]1CC[C@]2(C)[C @H](CC[C@H](C)[C@@]23CCC( =O) O3) C1(C)C Q105025376 3. Results and Discussions 3.1. Structural validation and quality assessment of 2VWD Ramachandran plot and Verify3D along with ERRAT score were used to assess the overall structural quality of the protein(51,52). Fig. 3 shows the Ramachandran plot with a high majority of protein residues in the most favoured region indicated by green, which is a very positive sign indicating that the protein’s structure is energetically stable and welldefined. Very few points are in red, that is the disallowed region. Some of the residues in this region might be acceptable if they belong to flexible loops. The overall quality of the protein structure is good as suggested by the Ramachandran plot obtained from Discovery Studio Visualizer. GSC Biological and Pharmaceutical Sciences, 2025, 33(01), 344-363 349 Figure 3 Ramachandran plot of the attachment glycoprotein of NiV (PDB ID2VWD) Verify3D plot is used to check if the 3D structure of the protein complies with the 1D sequence and if the amino acid residues are in an energetically favoured environment(48,53). Positive values indicate a favourable environment, whereas negative values don’t. A large majority of the scores for the residues are positive, as seen in Fig. 4, suggesting that the overall fold of the protein shows consistency with its 1D sequence, meaning they have a higher 3D-1D score. Although there are certain dips below zero, the overall quality of the protein structure based on sequence is good since 80.92% of the amino acids have the same 3D environment as suggested by the sequence, because they scored above 0.1, which is considered the threshold of acceptability. Thus, the verify3D plot also suggests that the protein structure meets the criteria for a good quality protein and hence, can be taken ahead for further studies. Lastly, on ERRAT, the protein structure was run and the overall quality factor of the protein structure was 93.4949 out of 100, indicating very highquality protein. GSC Biological and Pharmaceutical Sciences, 2025, 33(01), 344-363 350 Figure 4 Verify3D plot for chain A and B of the attachment glycoprotein of NiV (PDB ID2VWD) 3.2. Virtual Screening For 10 Indian medicinal plants, namely Patala (Stereospermum suaveolens), Shalaparni (Desmodium gangeticum), Musta (Cyperus rotundus), Chirayata (Swertia chirata), Guduchi (Tinospora cordifolia), Bhunimba (Andrographis paniculata), Patha (Cissampelos pareira), Vasaka (Justicia adhatoda), Agnimantha (Clerodendrum phlomidis) and Nirgundi (Vitex negundo), 959 phytochemicals were listed down from the IMPPAT database. Post elimination of duplicates, 470 remained. Docking of all these 470 phytochemicals and the standard was done with the Attachment Glycoprotein (2VWD) of Nipah virus. Results obtained from docking showed that out of these 470, 180 demonstrated better binding affinity than the standard-Ribavirin, which showed binding affinity = -6.6 kcal/mol. The toxicity classes of all these compounds were checked using ProTox-3.0 software. Compounds with toxicity classes 5 and 6 were screened out. 32 such compounds were found, out of which 27 were blood-brain barrier permeant, not a P-gap substrate and were druglike. Only 2 did not inhibit the CYP450 enzymes. Lastly, only 1 compound, Videoin B (L2), complied with the original docking score on redocking individually, while the other did not. These 7 levels of screening are shown in Fig. 5. Hence, for Vitedoin B similar structure search was done with the help of PubChem and LOTUS databases, resulting in the selection of L1 and L3 as 2 non-planar stereoisomers of L2 Figure 5 Various stages of Virtual Screening for Niv Lead Compound discovery GSC Biological and Pharmaceutical Sciences, 2025, 33(01), 344-363 351 3.3. Docking results analysis Figure 6 Best docked posed of L0, L1, L2 and L3 with protein 2VWD 3.3.1. Quantitative and comparative data analysis of binding affinities Table 2 enlists the binding score, type of interactions between the ligand and the interacting amino acid residues and the binding site in which L0, L1, L2 and L3 are present. Fig. 6 shows the ligands bound in the binding pockets of the protein-2VWD, an enlarged view of the binding site and the 2D diagram showing different interactions present in the protein-ligand complex formation. L0 has a binding affinity of - 6.6 kcal/mol. L1 has a binding affinity - 6.7 kcal/mol. There is a difference of -0.1 units in the binding affinities of L0 and L1. L2 and L3 show significantly higher negative values of binding affinity than L0. L2 exhibits -7.5 and L3 shows -7.8 kcal/mol. GSC Biological and Pharmaceutical Sciences, 2025, 33(01), 344-363 352 Table 2 Binding affinities, interaction types and binding site coordinates for protein in complexation with L0, L1, L2 and L3 Protein complexed with Binding affinity (in kcal/mol) Type of interactions Binding site coordinates (x, y, z) L0 -6.6 Unfavourable donor-donor Van der Waals Conventional hydrogen Carbon hydrogen Pi-cation Pi-donor hydrogen Pi-alkyl -47.006413, -9.721968, -24.949323 L1 -6.7 Van der Waals Conventional hydrogen -42.043783, -1.941174, -16.125174 L2 -7.5 Van der Waals Conventional hydrogen -14.592783, -29.771478, -25.868087 L3 -7.8 Van der Waals Conventional hydrogen Carbon hydrogen -41.927783, -1.905391, -16.008435 3.3.2. Structural differences and their impact Figure 7 Common 2D diagram for L1, L2 and L3 with stereocenters Three important key parameters affecting the binding affinity are planarity, stereochemistry and binding site coordinates. As seen in Table 2, L1, L2 and L3 share the same molecular formula C19H30O4 and the same atom connectivity, but they have different spatial arrangements. Since all stereoisomers have different 3D diagrams but share the same 2D diagram, in Fig. 7, the Common 2D diagram for L1, L2, and L3 has been given with their stereocenters highlighted in green. There are 5 stereocenters for L1, L2 and L3 as mentioned in Table 3 and seen in Fig. 7. In L2, all the groups at the stereocenters lie in the plane of the paper, hence it demonstrates a planar structure, limiting its interactions to chain A of 2VWD. The 5 stereocenters in L1, L2, and L3 are C-1, C-2, C-4a, C-6 and C-8a where C1 is the spiro carbon atom connecting the naphthalene ring to the oxolan ring; C2 is the carbon atom bearing the methyl group on the naphthalene ring; C4a is the bridgehead carbon atom present between the two rings of the naphthalene; C6 bears the acetate group on the naphthalene ring and C8a again is the bridgehead carbon but it bears the methyl group on the naphthalene ring. For L1, stereochemistry is 1R,2R,4aS,6S,8aS as indicated by the name of the compound in Table 1. If 1R becomes 1S, 2R becomes 2S, 4aS becomes 4aR, 6S becomes 6R and 8aS becomes 8aR, that is, if the stereochemistry at the stereocenters of L1 is inverted, the resulting compound would be L3. Therefore, L1 and L3 are non-planar GSC Biological and Pharmaceutical Sciences, 2025, 33(01), 344-363 359 [4] Randhawa V, Pathania S, Kumar M. 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