{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T18:10:59Z","timestamp":1784657459353,"version":"3.55.0"},"reference-count":55,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T00:00:00Z","timestamp":1714435200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"King Abdullah University of Science and Technology (KAUST)","award":["FCC\/1\/1976-09-01"],"award-info":[{"award-number":["FCC\/1\/1976-09-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Favipiravir (FP) and ebselen (EB) belong to a diverse class of antiviral drugs known for their significant efficacy in treating various viral infections. Utilizing molecular dynamics (MD) simulations, machine learning, and van der Waals density functional theory, we accurately elucidate the binding properties of these antiviral drugs on a phosphorene single-layer. To further investigate these characteristics, this study employs four distinct machine learning models\u2014Random Forest, Gradient Boosting, XGBoost, and CatBoost. The Hamiltonian of antiviral molecules within a monolayer of phosphorene is appropriately trained. The key aspect of utilizing machine learning (ML) in drug design revolves around training models that are efficient and precise in approximating density functional theory (DFT). Furthermore, the study employs SHAP (SHapley Additive exPlanations) to elucidate model predictions, providing insights into the contribution of each feature. To explore the interaction characteristics and thermodynamic properties of the hybrid drug, we employ molecular dynamics and DFT calculations in a vacuum interface. Our findings suggest that this functionalized 2D complex exhibits robust thermostability, indicating its potential as an effective and enabled entity. The observed variations in free energy at different surface charges and temperatures suggest the adsorption potential of FP and EB molecules from the surrounding environment.<\/jats:p>","DOI":"10.3390\/ijms25094897","type":"journal-article","created":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T03:30:49Z","timestamp":1714534249000},"page":"4897","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Exploring Antiviral Drugs on Monolayer Black Phosphorene: Atomistic Theory and Explainable Machine Learning-Assisted Platform"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7844-3029","authenticated-orcid":false,"given":"Slimane","family":"Laref","sequence":"first","affiliation":[{"name":"Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2138-319X","authenticated-orcid":false,"given":"Fouzi","family":"Harrou","sequence":"additional","affiliation":[{"name":"Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6703-4270","authenticated-orcid":false,"given":"Ying","family":"Sun","sequence":"additional","affiliation":[{"name":"Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7108-3574","authenticated-orcid":false,"given":"Xin","family":"Gao","sequence":"additional","affiliation":[{"name":"Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Gojobori","sequence":"additional","affiliation":[{"name":"Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1038\/nnano.2015.17","article-title":"Breaking the depth dependency of phototherapy with Cerenkov radiation and low-radiance-responsive nanophotosensitizers","volume":"10","author":"Kotagiri","year":"2015","journal-title":"Nat. Nanotechnol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1038\/nm.2995","article-title":"Multifunctional in vivo vascular imaging using near-infrared II fluorescence","volume":"18","author":"Hong","year":"2012","journal-title":"Nat. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1039\/C2CS35342C","article-title":"Nano-graphene in biomedicine: Theranostic applications","volume":"42","author":"Yang","year":"2013","journal-title":"Chem. Soc. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/nrc1566","article-title":"Cancer nanotechnology: Opportunities and challenges","volume":"5","author":"Ferrari","year":"2005","journal-title":"Nat. Rev. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1800518","DOI":"10.1002\/advs.201800518","article-title":"Insights into 2D MXenes for versatile biomedical applications: Current advances and challenges ahead","volume":"5","author":"Lin","year":"2018","journal-title":"Adv. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.cplett.2013.07.033","article-title":"Characterization of graphene\u2013fullerene interactions: Insights from density functional theory","volume":"582","author":"Laref","year":"2013","journal-title":"Chem. Phys. Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"022001","DOI":"10.1088\/2053-1583\/ab1e0a","article-title":"Production and processing of graphene and related materials","volume":"7","author":"Backes","year":"2020","journal-title":"2D Mater."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3518","DOI":"10.1021\/nl301061b","article-title":"Artificially stacked atomic layers: Toward new van der Waals solids","volume":"12","author":"Gao","year":"2012","journal-title":"Nano Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/nature11458","article-title":"A roadmap for graphene","volume":"490","author":"Novoselov","year":"2012","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7714","DOI":"10.1002\/anie.201403335","article-title":"Classification framework for graphene-based materials","volume":"53","author":"Wick","year":"2014","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.apsusc.2019.05.214","article-title":"Impact of phosphorous and sulphur substitution on Dirac cone modification and optical behaviors of monolayer graphene for nano-electronic devices","volume":"489","author":"Laref","year":"2019","journal-title":"Appl. Surf. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"163755","DOI":"10.1016\/j.ijleo.2019.163755","article-title":"Electronic structure and optical characteristics of AA stacked bilayer graphene: A first principles calculations","volume":"206","author":"Laref","year":"2020","journal-title":"Optik"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/nnano.2010.235","article-title":"Freestanding palladium nanosheets with plasmonic and catalytic properties","volume":"6","author":"Huang","year":"2011","journal-title":"Nat. Nanotechnol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"16098","DOI":"10.1038\/natrevmats.2016.98","article-title":"2D metal carbides and nitrides (MXenes) for energy storage","volume":"2","author":"Anasori","year":"2017","journal-title":"Nat. Rev. Mater."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Laref, S., Wang, B., Inal, S., Al-Ghamdi, S., Gao, X., and Gojobori, T. (2022). A Peculiar Binding Characterization of DNA (RNA) Nucleobases at MoOS-Based Janus Biosensor: Dissimilar Facets Role on Selectivity and Sensitivity. Biosensors, 12.","DOI":"10.3390\/bios12070442"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6224","DOI":"10.1039\/C9CS00822E","article-title":"Degradation-by-design: How chemical functionalization enhances the biodegradability and safety of 2D materials","volume":"49","author":"Ma","year":"2020","journal-title":"Chem. Soc. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2732","DOI":"10.1039\/C4CS00257A","article-title":"Semiconducting black phosphorus: Synthesis, transport properties and electronic applications","volume":"44","author":"Liu","year":"2015","journal-title":"Chem. Soc. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Shen, L., Li, B., and Qiao, Y. (2018). Fe3O4 nanoparticles in targeted drug\/gene delivery systems. Materials, 11.","DOI":"10.3390\/ma11020324"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"146577","DOI":"10.1016\/j.apsusc.2020.146577","article-title":"BC3 graphene-like monolayer as a drug delivery system for nitrosourea anticancer drug: A first-principles perception","volume":"525","author":"Rahimi","year":"2020","journal-title":"Appl. Surf. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"345401","DOI":"10.1088\/1361-6463\/aad3e8","article-title":"Covalent organic framework as smart and high efficient carrier for anticancer drug delivery: A DFT calculations and molecular dynamics simulation study","volume":"51","author":"Hashemzadeh","year":"2018","journal-title":"J. Phys. D Appl. Phys."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1021\/acscentsci.0c00272","article-title":"Research and development on therapeutic agents and vaccines for COVID-19 and related human coronavirus diseases","volume":"6","author":"Liu","year":"2020","journal-title":"ACS Cent. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/s41586-020-2223-y","article-title":"Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors","volume":"582","author":"Jin","year":"2020","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3767","DOI":"10.1007\/s13204-022-02528-0","article-title":"Neural artificial networking for nonlinear Darcy\u2013Forchheimer nanofluidic slip flow","volume":"13","author":"Khan","year":"2023","journal-title":"Appl. Nanosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"105730","DOI":"10.1016\/j.icheatmasstransfer.2021.105730","article-title":"Intelligent backpropagated neural networks application on Darcy-Forchheimer ferrofluid slip flow system","volume":"129","author":"Shoaib","year":"2021","journal-title":"Int. Commun. Heat Mass Transf."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.matcom.2022.05.004","article-title":"Intelligent neuro-computing for entropy generated Darcy\u2013Forchheimer mixed convective fluid flow","volume":"201","author":"Raja","year":"2022","journal-title":"Math. Comput. Simul."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Varun Kumar, R., Alsulami, M., Sarris, I., Prasannakumara, B., and Rana, S. (2023). Backpropagated Neural Network Modeling for the Non-Fourier Thermal Analysis of a Moving Plate. Mathematics, 11.","DOI":"10.3390\/math11020438"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1140\/epjp\/s13360-023-03680-4","article-title":"Numerical and Levenberg\u2013Marquardt backpropagation neural networks computation of ternary nanofluid flow across parallel plates with Nield boundary conditions","volume":"138","author":"Sharma","year":"2023","journal-title":"Eur. Phys. J. Plus"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1080\/08927022.2020.1808215","article-title":"COMPASS III: Automated fitting workflows and extension to ionic liquids","volume":"47","author":"Akkermans","year":"2021","journal-title":"Mol. Simul."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Laref, S., Wang, B., Gao, X., and Gojobori, T. (2023). Computational Studies of Auto-Active van der Waals interaction Molecules on Ultra-thin Black-Phosphorus Film. Molecules, 28.","DOI":"10.3390\/molecules28020681"},{"key":"ref_30","unstructured":"Hoffman, P., Grinstein, G., Marx, K., Grosse, I., and Stanley, E. (1997, January 24). DNA visual and analytic data mining. Proceedings of the Proceedings. Visualization\u201997 (Cat. No. 97CB36155), Phoenix, AZ, USA."},{"key":"ref_31","unstructured":"Harrou, F., Sun, Y., Hering, A.S., Madakyaru, M., and Dairi, A. (2021). Statistical Process Monitoring Using Advanced Data-Driven and Deep Learning Approaches, Elsevier."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Laref, S., Harrou, F., Wang, B., Sun, Y., Laref, A., Laleg-Kirati, T.M., Gojobori, T., and Gao, X. (2023). Synergy of Small Antiviral Molecules on a Black-Phosphorus Nanocarrier: Machine Learning and Quantum Chemical Simulation Insights. Molecules, 28.","DOI":"10.3390\/molecules28083521"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/s42256-019-0138-9","article-title":"From local explanations to global understanding with explainable AI for trees","volume":"2","author":"Lundberg","year":"2020","journal-title":"Nat. Mach. Intell."},{"key":"ref_34","unstructured":"Lundberg, S.M., and Lee, S.I. (2017, January 4\u20139). A unified approach to interpreting model predictions. Proceedings of the 31st International Conference on Neural Information Processing Systems, Long Beach, CA, USA."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"101930","DOI":"10.1016\/j.rineng.2024.101930","article-title":"Explainable machine learning methods for predicting water treatment plant features under varying weather conditions","volume":"21","author":"Harrou","year":"2024","journal-title":"Results Eng."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1023\/A:1010933404324","article-title":"Random forests","volume":"45","author":"Breiman","year":"2001","journal-title":"Mach. Learn."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Jiang, R., Tang, W., Wu, X., and Fu, W. (2009). A random forest approach to the detection of epistatic interactions in case-control studies. BMC Bioinform., 10.","DOI":"10.1186\/1471-2105-10-S1-S65"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Villegas-Mier, C.G., Rodriguez-Resendiz, J., \u00c1lvarez-Alvarado, J.M., Jim\u00e9nez-Hern\u00e1ndez, H., and Odry, \u00c1. (2022). Optimized random forest for solar radiation prediction using sunshine hours. Micromachines, 13.","DOI":"10.3390\/mi13091406"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1006\/jcss.1997.1504","article-title":"A decision-theoretic generalization of on-line learning and an application to boosting","volume":"55","author":"Freund","year":"1997","journal-title":"J. Comput. Syst. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Hastie, T., Tibshirani, R., Friedman, J.H., and Friedman, J.H. (2009). The Elements of Statistical Learning: Data Mining, Inference, and Prediction, Springer.","DOI":"10.1007\/978-0-387-84858-7"},{"key":"ref_41","first-page":"100333","article-title":"Comparison of decision tree based ensemble methods for prediction of photovoltaic maximum current","volume":"16","author":"Omer","year":"2022","journal-title":"Energy Convers. Manag. X"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Chen, T., and Guestrin, C. (2016, January 13\u201317). Xgboost: A scalable tree boosting system. Proceedings of the 22nd Acm Sigkdd International Conference on Knowledge Discovery and Data Mining, San Francisco, CA, USA.","DOI":"10.1145\/2939672.2939785"},{"key":"ref_43","first-page":"1","article-title":"CatBoost: Unbiased boosting with categorical features","volume":"31","author":"Prokhorenkova","year":"2018","journal-title":"Adv. Neural Inf. Process. Syst."},{"key":"ref_44","unstructured":"Dorogush, A.V., Ershov, V., and Gulin, A. (2018). CatBoost: Gradient boosting with categorical features support. arXiv."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3436","DOI":"10.1109\/TGRS.2008.2001756","article-title":"On the exploitation of target statistics for SAR interferometry applications","volume":"46","author":"Guarnieri","year":"2008","journal-title":"IEEE Trans. Geosci. Remote Sens."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1186\/s40537-020-00369-8","article-title":"CatBoost for big data: An interdisciplinary review","volume":"7","author":"Hancock","year":"2020","journal-title":"J. Big Data"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3745","DOI":"10.1007\/s11269-023-03525-w","article-title":"A Comprehensive Experimental and Computational Investigation on Estimation of Scour Depth at Bridge Abutment: Emerging Ensemble Intelligent Systems","volume":"37","author":"Pandey","year":"2023","journal-title":"Water Resour. Manag."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/0927-0256(96)00008-0","article-title":"Efficiency of ab-initio total energy calculations for metals and semiconductors using a plane-wave basis set","volume":"6","author":"Kresse","year":"1996","journal-title":"Comput. Mater. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"11169","DOI":"10.1103\/PhysRevB.54.11169","article-title":"Efficient iterative schemes for ab initio total-energy calculations using a plane-wave basis set","volume":"54","author":"Kresse","year":"1996","journal-title":"Phys. Rev. B"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.1103\/PhysRevB.59.1758","article-title":"From ultrasoft pseudopotentials to the projector augmented-wave method","volume":"59","author":"Kresse","year":"1999","journal-title":"Phys. Rev. B"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1002\/jcc.21759","article-title":"Effect of the damping function in dispersion corrected density functional theory","volume":"32","author":"Grimme","year":"2011","journal-title":"J. Comput. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1002\/jcc.20078","article-title":"Accurate description of van der Waals complexes by density functional theory including empirical corrections","volume":"25","author":"Grimme","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3865","DOI":"10.1103\/PhysRevLett.77.3865","article-title":"Generalized gradient approximation made simple","volume":"77","author":"Perdew","year":"1996","journal-title":"Phys. Rev. Lett."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"154104","DOI":"10.1063\/1.3382344","article-title":"A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu","volume":"132","author":"Grimme","year":"2010","journal-title":"J. Chem. Phys."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1002\/jcc.20495","article-title":"Semiempirical GGA-type density functional constructed with a long-range dispersion correction","volume":"27","author":"Grimme","year":"2006","journal-title":"J. Comput. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/9\/4897\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:37:11Z","timestamp":1760107031000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/9\/4897"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,30]]},"references-count":55,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["ijms25094897"],"URL":"https:\/\/doi.org\/10.3390\/ijms25094897","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,30]]}}}