Enteroviruses remain a stubborn gap in modern antiviral medicine. Despite decades of research, no virus-specific therapy against this broad group of pathogens has been approved by regulatory agencies, leaving clinicians to manage infections ranging from mild respiratory illness to myocarditis, encephalitis and acute flaccid myelitis with supportive care alone. A new computational study published in BMC Methods now reports a detailed molecular modelling campaign on novel derivatives of pleconaril, one of the most extensively studied capsid-binding antienteroviral candidates, in an effort to identify promising lead compounds for future drug development.
The research, led by Chetan Palvi, Snehal Ukhade, Isha S. Ingle and Hemchandra K. Chaudhari with Sanchali S. Gadade, assembled a ligand library of twenty-four novel pleconaril derivatives drawn from the literature, each with reported antienteroviral activity. Using the PHASE module of the Schrödinger modelling suite, the team built atom-based and field-based three-dimensional quantitative structure-activity relationship (3D-QSAR) models, generated a common pharmacophore hypothesis, docked every compound into the capsid protein of enterovirus D68 and estimated binding free energies with the MM/GBSA method. Molecular properties and absorption, distribution, metabolism and excretion parameters were assessed with the QikProp utility and SwissADME.
The biological target was chosen with care. The crystal structure of human enterovirus D68 in complex with pleconaril, deposited in the Protein Data Bank under the identifier 4WM7, was resolved at 2.32 angstroms and imported into Maestro for preparation. Bound ligands, cofactors and water molecules were removed, side chains that did not participate in the binding cavity were neutralised with the OPLS_2005 force field, and hydrogen atoms were added. The quality of the prepared structure was checked with a Ramachandran plot before docking grids were generated around the centroid of the co-crystallised ligand.
Enteroviruses belong to the Enterovirus genus of the Picornaviridae family and comprise roughly one hundred serotypes across species A to D. This diversity is a major obstacle to vaccination: the only vaccines currently available target poliomyelitis caused by polioviruses, two inactivated enterovirus A71 vaccines used in China against hand-foot-and-mouth disease, and a vaccine against the foot-and-mouth disease virus of livestock. Small molecules that attack conserved steps of the viral life cycle therefore address a significant unmet clinical need, and the capsid’s hydrophobic pocket has long been viewed as an attractive point of attack.
That pocket normally holds a fatty acid known as the pocket factor, which is expelled when the virus attaches to a host cell. The resulting conformational changes in the capsid facilitate the release of the viral genomic RNA. Capsid-binding inhibitors compete with the pocket factor for occupancy of the hydrophobic cavity and can block viral attachment or uncoating. Pleconaril, vapendavir and pocapavir are among the most extensively studied candidates exploiting this mechanism, yet none has reached clinical approval, which is precisely why the authors focused their modelling effort on pleconaril analogues.
The clinical setbacks in this drug class are instructive. Pleconaril was not approved by the US Food and Drug Administration for treating the common cold because of adverse effects including headache, diarrhoea and nausea, its induction of the cytochrome P-450 enzyme CYP3A4, which accelerates the metabolism of ethinyl estradiol, and the emergence of pleconaril-resistant viruses. In February 2017, vapendavir failed in a phase IIb trial owing to insufficient efficacy against rhinoviruses compared with placebo. In a randomised, blinded, placebo-controlled study of poliovirus-infected patients treated with pocapavir, resistance was recorded in 44 percent of the treated group versus 10 percent of the placebo group. Developing effective, selective and broad-spectrum antienteroviral agents remains a key focus for medicinal chemists.
Against this backdrop, the docking results provide the study’s headline numbers. The 12b complex with 4WM7 also yielded a favourable Prime MM/GBSA binding free energy of minus 111.54 kilocalories per mole, which the authors report as superior to the complexes formed with the reference standards. Structural analysis of the docked poses indicated pi-pi stacking interactions between the isoxazole ring of the derivatives and the residue TYR193 within the binding site.
Validation of the docking protocol was built into the workflow. The co-crystallised native ligand was re-docked into its binding site, and the resulting root-mean-square-deviation values of less than 2 angstroms confirmed that the procedure reproduced the experimentally observed binding mode. Scoring was performed in Glide’s Extra Precision mode, and all twenty-four compounds were allowed to dock into the same cavity. Swiss Target Prediction was then applied to the best-docked molecule, 12b, suggesting probable engagement of four target families: kinases at 60 percent, enzymes at 13.3 percent, and G-protein coupled receptors and proteases at 6.7 percent each.
The pharmacophore work distilled the activity data into a spatial template. Ligands with a pIC50 value above 6.3 were classed as active and those below as inactive, yielding seventeen active and seven inactive compounds. Twenty hypotheses were generated, and the top-ranked six-point model, designated AHHRRR_1, was selected on the basis of a site score of 0.917, a phase hyposcore of 1.337 and a survival score of 5.610. The model combines one hydrogen bond acceptor feature, two hydrophobic features and three aromatic ring features, and every active compound in the dataset could be aligned onto it, offering a blueprint for designing future analogues.
Leave-one-out cross-validation was used to assess stability and robustness, while RMSE, Q2 and Pearson’s r values for the test set quantified predictive power. The contour maps localise the structure-activity signals: blue cubes around the 5-amidoisoxazole moiety suggest that electron-withdrawing capability there may benefit activity, whereas red cubes over the pyridine region warn that further electron-withdrawing substitution could hinder it. In the field-based maps, a favoured electropositive zone surrounds the carboxylic portion attached to the isoxazole ring, a favourable steric region encircles the pyridine ring, and hydrophobic substitution near the pyridine core correlates with intermediate activity.
The ADME screening added a drug-like filter to the computational picture. QikProp calculations showed that all compounds, with a few exceptions, fell within reasonable ranges for molecular properties, the rule-of-five values lay within acceptable limits, and the predicted percentage of human oral absorption exceeded 85 percent for most molecules. One outlier illustrates the practical limits of such predictions: molecule 12c, the weakest docked compound, contains an ester and an imine that can hydrolyse at high or low pH, so QikProp could not produce data for it, and the profile of the second-to-last molecule, 19, was reported instead.
The authors are careful to frame the work as computational hypothesis generation rather than proof of therapeutic value. Docking scores, MM/GBSA energies and QSAR statistics rank and rationalise compounds against a single crystal structure; they do not demonstrate antiviral efficacy in infected cells, animals or patients, and the twenty-four-compound dataset is modest by QSAR standards. The value of the study lies in the tools it leaves behind: validated atom-based and field-based 3D-QSAR models, a six-point pharmacophore that all active ligands satisfy, and a comparative docking map of the capsid pocket that together could guide the design of the next generation of pleconaril derivatives as candidate antienteroviral medicines.
Subject of Research: Molecular modelling of novel pleconaril derivatives as potential antienteroviral agents targeting the enterovirus D68 capsid
Article Title: Molecular modelling studies on novel pleconaril derivatives as antienteroviral agents
Article References: Palvi, C., Ukhade, S., Ingle, I. S., Gadade, S. S., & Chaudhari, H. K. (2026). Molecular modelling studies on novel pleconaril derivatives as antienteroviral agents. BMC Methods, 3(1), Article 25. https://doi.org/10.1186/s44330-026-00065-8
Image Credits: AI Generated
DOI: 10.1186/s44330-026-00065-8
Keywords: enterovirus D68, pleconaril, 3D-QSAR, molecular docking, pharmacophore modelling, MM/GBSA, capsid-binding inhibitors, ADME prediction, drug design, antiviral research, computational chemistry, BMC Methods
News Source: Gregory Coleman. (October 29, 2026). Computational models point to pleconaril derivatives as candidate antienteroviral agents. Scienmag.
