{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T04:57:58Z","timestamp":1773982678720,"version":"3.50.1"},"reference-count":39,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T00:00:00Z","timestamp":1641945600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Computation"],"abstract":"<jats:p>The unprecedented global health threat of SARS-CoV-2 has sparked a continued interest in discovering novel anti-COVID-19 agents. To this end, we present here a computer-based protocol for identifying potential compounds targeting RNA-dependent RNA polymerase (RdRp). Starting from our previous study wherein, using a virtual screening campaign, we identified a fumiquinazolinone alkaloid quinadoline B (Q3), an antiviral fungal metabolite with significant activity against SARS-CoV-2 RdRp, we applied in silico combinatorial methodologies for generating and screening a library of anti-SARS-CoV-2 candidates with strong in silico affinity for RdRp. For this study, the quinadoline pharmacophore was subjected to structural iteration, obtaining a Q3-focused library of over 900,000 unique structures. This chemical library was explored to identify binders of RdRp with greater affinity with respect to the starting compound Q3. Coupling this approach with the evaluation of physchem profile, we found 26 compounds with significant affinities for the RdRp binding site. Moreover, top-ranked compounds were submitted to molecular dynamics to evaluate the stability of the systems during a selected time, and to deeply investigate the binding mode of the most promising derivatives. Among the generated structures, five compounds, obtained by inserting nucleotide-like scaffolds (1, 2, and 5), heterocyclic thiazolyl benzamide moiety (compound 3), and a peptide residue (compound 4), exhibited enhanced binding affinity for SARS-CoV-2 RdRp, deserving further investigation as possible antiviral agents. Remarkably, the presented in silico procedure provides a useful computational procedure for hit-to-lead optimization, having implications in anti-SARS-CoV-2 drug discovery and in general in the drug optimization process.<\/jats:p>","DOI":"10.3390\/computation10010007","type":"journal-article","created":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T09:10:36Z","timestamp":1641978636000},"page":"7","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Virtual Combinatorial Library Screening of Quinadoline B Derivatives against SARS-CoV-2 RNA-Dependent RNA Polymerase"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9375-6242","authenticated-orcid":false,"given":"Simone","family":"Brogi","sequence":"first","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark Tristan","family":"Quimque","sequence":"additional","affiliation":[{"name":"Laboratory for Organic Reactivity, Discovery and Synthesis (LORDS), Research Center for the Natural and Applied Sciences, University of Santo Tomas, Espa\u00f1a Blvd., Manila 1015, Philippines"},{"name":"The Graduate School, University of Santo Tomas, Espa\u00f1a Blvd., Manila 1015, Philippines"},{"name":"Chemistry Department, College of Science and Mathematics, Mindanao State University\u2014Iligan Institute of Technology, Tibanga, Iligan City 9200, Philippines"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6055-0886","authenticated-orcid":false,"given":"Kin Israel","family":"Notarte","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Surgery, University of Santo Tomas, Espana Blvd., Manila 1015, Philippines"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremiah Gabriel","family":"Africa","sequence":"additional","affiliation":[{"name":"Laboratory for Organic Reactivity, Discovery and Synthesis (LORDS), Research Center for the Natural and Applied Sciences, University of Santo Tomas, Espa\u00f1a Blvd., Manila 1015, Philippines"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jenina Beatriz","family":"Hernandez","sequence":"additional","affiliation":[{"name":"Laboratory for Organic Reactivity, Discovery and Synthesis (LORDS), Research Center for the Natural and Applied Sciences, University of Santo Tomas, Espa\u00f1a Blvd., Manila 1015, Philippines"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophia Morgan","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, College of Science, University of Santo Tomas, Espa\u00f1a Blvd., Manila 1015, Philippines"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincenzo","family":"Calderone","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7972-106X","authenticated-orcid":false,"given":"Allan Patrick","family":"Macabeo","sequence":"additional","affiliation":[{"name":"Laboratory for Organic Reactivity, Discovery and Synthesis (LORDS), Research Center for the Natural and Applied Sciences, University of Santo Tomas, Espa\u00f1a Blvd., Manila 1015, Philippines"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e667","DOI":"10.1016\/S2589-7500(20)30192-8","article-title":"Artificial intelligence in COVID-19 drug repurposing","volume":"2","author":"Zhou","year":"2020","journal-title":"Lancet Digit. Health"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.3389\/fphar.2020.01013","article-title":"Turning the Tide: Natural Products and Natural-Product-Inspired Chemicals as Potential Counters to SARS-CoV-2 Infection","volume":"11","author":"Wang","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Abdallah, H.M., El-Halawany, A.M., Sirwi, A., El-Araby, A.M., Mohamed, G.A., Ibrahim, S.R.M., Koshak, A.E., Asfour, H.Z., Awan, Z.A., and Elfaky, M.A. (2021). Repurposing of Some Natural Product Isolates as SARS-COV-2 Main Protease Inhibitors via In Vitro Cell Free and Cell-Based Antiviral Assessments and Molecular Modeling Approaches. Pharmaceuticals, 14.","DOI":"10.3390\/ph14030213"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"107408","DOI":"10.1016\/j.compbiolchem.2020.107408","article-title":"Interaction of small molecules with the SARS-CoV-2 main protease in silico and in vitro validation of potential lead compounds using an enzyme-linked immunosorbent assay","volume":"89","author":"Pitsillou","year":"2020","journal-title":"Comput. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"146","DOI":"10.2174\/157340911795677602","article-title":"Molecular docking: A powerful approach for structure-based drug discovery","volume":"7","author":"Meng","year":"2011","journal-title":"Curr. Comput. Aided Drug Des."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Bharadwaj, S., El-Kafrawy, S.A., Alandijany, T.A., Bajrai, L.H., Shah, A.A., Dubey, A., Sahoo, A.K., Yadava, U., Kamal, M.A., and Azhar, E.I. (2021). Structure-Based Identification of Natural Products as SARS-CoV-2 M(pro) Antagonist from Echinacea angustifolia Using Computational Approaches. Viruses, 13.","DOI":"10.3390\/v13020305"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Hajbabaie, R., Harper, M.T., and Rahman, T. (2021). Establishing an Analogue Based In Silico Pipeline in the Pursuit of Novel Inhibitory Scaffolds against the SARS Coronavirus 2 Papain-Like Protease. Molecules, 26.","DOI":"10.3390\/molecules26041134"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/s41598-020-79918-3","article-title":"ABBV-744 as a potential inhibitor of SARS-CoV-2 main protease enzyme against COVID-19","volume":"11","author":"Fakhar","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"612","DOI":"10.3389\/fchem.2020.00612","article-title":"Editorial: In silico Methods for Drug Design and Discovery","volume":"8","author":"Brogi","year":"2020","journal-title":"Front. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Yadav, R., Chaudhary, J.K., Jain, N., Chaudhary, P.K., Khanra, S., Dhamija, P., Sharma, A., Kumar, A., and Handu, S. (2021). Role of Structural and Non-Structural Proteins and Therapeutic Targets of SARS-CoV-2 for COVID-19. Cells, 10.","DOI":"10.3390\/cells10040821"},{"key":"ref_11","unstructured":"Quimque, M.T., Notarte, K.I., Adviento, X.A., Cabunoc, M.H., de Leon, V.N., Delos Reyes, F.S.L., Lugtu, E.J., Manzano, J.A., Monton, S.N., and Munoz, J.E. (2022). Polyphenolic Natural Products Active In Silico against SARS-CoV-2 Spike Receptor Binding Domains and Non-Structural Proteins\u2014A Review. Comb. Chem. High Throughput Screen., 25."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1186\/s43141-021-00206-2","article-title":"Anti-HIV reverse transcriptase plant polyphenolic natural products with in silico inhibitory properties on seven non-structural proteins vital in SARS-CoV-2 pathogenesis","volume":"19","author":"Manzano","year":"2021","journal-title":"J. Genet. Eng. Biotechnol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Fernandez, R.A., Quimque, M.T., Notarte, K.I., Manzano, J.A., Pilapil, D.Y.t., de Leon, V.N., San Jose, J.J., Villalobos, O., Muralidharan, N.H., and Gromiha, M.M. (2021). Myxobacterial depsipeptide chondramides interrupt SARS-CoV-2 entry by targeting its broad, cell tropic spike protein. J. Biomol. Struct. Dyn., 1\u201312.","DOI":"10.26434\/chemrxiv.14043641"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1186\/s12967-020-02439-0","article-title":"Analysis of SARS-CoV-2 RNA-dependent RNA polymerase as a potential therapeutic drug target using a computational approach","volume":"18","author":"Aftab","year":"2020","journal-title":"J. Transl. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e04502","DOI":"10.1016\/j.heliyon.2020.e04502","article-title":"SARS-CoV-2 RNA Dependent RNA polymerase (RdRp)\u2013A drug repurposing study","volume":"6","author":"Ahmad","year":"2020","journal-title":"Heliyon"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"104591","DOI":"10.1016\/j.compbiomed.2021.104591","article-title":"In silico analysis of RNA-dependent RNA polymerase of the SARS-CoV-2 and therapeutic potential of existing antiviral drugs","volume":"135","author":"Mondal","year":"2021","journal-title":"Comput. Biol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4316","DOI":"10.1080\/07391102.2020.1776639","article-title":"Virtual screening-driven drug discovery of SARS-CoV2 enzyme inhibitors targeting viral attachment, replication, post-translational modification and host immunity evasion infection mechanisms","volume":"39","author":"Quimque","year":"2021","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11225","DOI":"10.1021\/ja9621760","article-title":"Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids","volume":"118","author":"Jorgensen","year":"1996","journal-title":"J. Am. Chem. Soc."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1126\/science.abb7498","article-title":"Structure of the RNA-dependent RNA polymerase from COVID-19 virus","volume":"368","author":"Gao","year":"2020","journal-title":"Science"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.ejmech.2015.12.044","article-title":"Synthesis and biological evaluation of fluorinated 1,5-diarylpyrrole-3-alkoxyethyl ether derivatives as selective COX-2 inhibitors endowed with anti-inflammatory activity","volume":"109","author":"Sticozzi","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.ejmech.2018.07.069","article-title":"Novel spiroindoline HDAC inhibitors: Synthesis, molecular modelling and biological studies","volume":"157","author":"Brindisi","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4650207","DOI":"10.1155\/2020\/4650207","article-title":"The Citrus Flavonoid Naringenin Protects the Myocardium from Ageing-Dependent Dysfunction: Potential Role of SIRT1","volume":"2020","author":"Testai","year":"2020","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2124","DOI":"10.1021\/acs.jmedchem.8b00099","article-title":"(S)-2-Amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)propanoic Acid (AMPA) and Kainate Receptor Ligands: Further Exploration of Bioisosteric Replacements and Structural and Biological Investigation","volume":"61","author":"Brogi","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1021\/acschemneuro.0c00195","article-title":"Ionotropic Glutamate Receptor GluA2 in Complex with Bicyclic Pyrimidinedione-Based Compounds: When Small Compound Modifications Have Distinct Effects on Binding Interactions","volume":"11","author":"Frydenvang","year":"2020","journal-title":"ACS Chem. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"574","DOI":"10.3389\/fchem.2019.00574","article-title":"Identification of Novel 3-Hydroxy-pyran-4-One Derivatives as Potent HIV-1 Integrase Inhibitors Using in silico Structure-Based Combinatorial Library Design Approach","volume":"7","author":"Sirous","year":"2019","journal-title":"Front. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3389\/fchem.2017.00007","article-title":"Computational Tool for Fast in silico Evaluation of hERG K(+) Channel Affinity","volume":"5","author":"Chemi","year":"2017","journal-title":"Front. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/j.ejmech.2016.10.064","article-title":"Identification of novel fluorescent probes preventing PrP(Sc) replication in prion diseases","volume":"127","author":"Zaccagnini","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1145\/1365490.1365500","article-title":"Scalable parallel programming with CUDA","volume":"6","author":"Nickolls","year":"2008","journal-title":"Queue"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of simple potential functions for simulating liquid water","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J. Chem. Phys."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.ejmech.2018.11.004","article-title":"Structure-activity relationships, biological evaluation and structural studies of novel pyrrolonaphthoxazepines as antitumor agents","volume":"162","author":"Brindisi","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1111\/cns.12290","article-title":"Disease-modifying anti-Alzheimer\u2019s drugs: Inhibitors of human cholinesterases interfering with beta-amyloid aggregation","volume":"20","author":"Brogi","year":"2014","journal-title":"CNS Neurosci. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6885","DOI":"10.1021\/j100078a035","article-title":"A Multiple-Time-Step Molecular Dynamics Algorithm for Macromolecules","volume":"98","author":"Humphreys","year":"1994","journal-title":"J. Phys. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1103\/PhysRevA.31.1695","article-title":"Canonical dynamics: Equilibrium phase-space distributions","volume":"31","author":"Hoover","year":"1985","journal-title":"Phys. Rev. A"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4177","DOI":"10.1063\/1.467468","article-title":"Constant pressure molecular dynamics algorithms","volume":"101","author":"Martyna","year":"1994","journal-title":"J. Chem. Phys."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"8577","DOI":"10.1063\/1.470117","article-title":"A smooth particle mesh Ewald method","volume":"103","author":"Essmann","year":"1995","journal-title":"J. Chem. Phys."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1016\/j.cmi.2020.04.023","article-title":"COVID-19 pandemic-a focused review for clinicians","volume":"26","author":"Cevik","year":"2020","journal-title":"Clin. MicroBiol. Infect."},{"key":"ref_38","unstructured":"(2021, July 25). Organic Chemistry Portal. Available online: http:\/\/www.organic-chemistry.org\/prog\/peo\/."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2719","DOI":"10.1021\/jm901137j","article-title":"New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays","volume":"53","author":"Baell","year":"2010","journal-title":"J. Med. Chem."}],"container-title":["Computation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-3197\/10\/1\/7\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:14:47Z","timestamp":1760364887000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-3197\/10\/1\/7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,12]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["computation10010007"],"URL":"https:\/\/doi.org\/10.3390\/computation10010007","relation":{"has-preprint":[{"id-type":"doi","id":"10.26434\/chemrxiv-2021-jv6rk","asserted-by":"object"}]},"ISSN":["2079-3197"],"issn-type":[{"value":"2079-3197","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,12]]}}}