{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T19:22:44Z","timestamp":1790796164342,"version":"4.1.0"},"reference-count":56,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T00:00:00Z","timestamp":1761696000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Human immunodeficiency virus (HIV-1) and SARS-CoV-2 continue to co-burden global health, motivating discovery of broad-spectrum small molecules. Conessine, a steroidal alkaloid, has reported membrane-active and antimicrobial properties but remains underexplored as a dual antiviral chemotype. To interrogate conessine\u2019s multi-target antiviral potential against key enzymatic and entry determinants of HIV-1 and SARS-CoV-2 and to benchmark performance versus approved comparators. Eight targets were modeled: HIV-1 reverse transcriptase (RT, 3V81), protease (PR, 1HVR), integrase (IN, 3LPT), gp120\u2013gp41 trimer (4NCO); and SARS-CoV-2 main protease (Mpro, 6LU7), papain-like protease (PLpro, 6W9C), RNA-dependent RNA polymerase (RdRp, 7BV2), spike RBD (6M0J). Ligands (conessine; positive controls: dolutegravir for HIV-1, nirmatrelvir for SARS-CoV-2) were prepared with standard protonation, minimized, and docked using AutoDock Vina v 1.2.0exhaustiveness 4; 20 poses). Binding modes were profiled in 2D\/3D. Protocol robustness was verified by re-docking co-crystallized ligands (RMSD \u2264 2.0 \u00c5). Atomistic MD (explicit TIP3P, OPLS4, 300 K\/1 atm, NPT; 50\u2013100 ns) assessed pose stability (RMSD\/RMSF), pocket compaction (Rg, volume), and interaction persistence; MM\/GBSA provided qualitative energy decomposition. ADMET was predicted in silico. Conessine showed coherent, hydrophobically anchored binding across both viral panels. Best docking scores (kcal\u00b7mol\u22121) were: HIV-1\u2014PR \u22126.910, RT \u22126.672, IN \u22125.733; SARS-CoV-2\u2014spike RBD \u22127.025, Mpro \u22125.745, RdRp \u22125.737, PLpro \u22125.024. Interaction maps were dominated by alkyl\/\u03c0-alkyl packing to catalytic corridors (e.g., PR Ile50\/Val82, RT Tyr181\/Val106; Mpro His41\/Met49; RBD L455\/F486\/Y489) with occasional carbon-\/water-mediated H-bonds guiding orientation. MD sustained low ligand RMSD (typically \u22641.6\u20132.2 \u00c5) and damped RMSF at catalytic loops, indicating pocket rigidification; MM\/GBSA trends (\u2248 \u221230 to \u221240 kcal\u00b7mol\u22121, dispersion-driven) supported persistent nonpolar stabilization. Benchmarks behaved as expected: dolutegravir bound strongly to IN (\u22126.070) and PR (\u22127.319) with stable MD; nirmatrelvir was specific for Mpro and displayed weaker, discontinuous engagement at PLpro\/RdRp\/RBD under identical settings. ADMET suggested conessine has excellent permeability\/BBB access (high logP), but liabilities include poor aqueous solubility, predicted hERG risk, and CYP2D6 substrate dependence.Conessine operates as a hydrophobic, multi-target wedge with the most favorable computed engagement at HIV-1 PR\/RT and the SARS-CoV-2 spike RBD, while maintaining stable poses at Mpro and RdRp. The scaffold merits medicinal-chemistry optimization to improve solubility and de-risk cardiotoxicity\/CYP interactions, followed by biochemical and cell-based validation against prioritized targets.<\/jats:p>","DOI":"10.3390\/v17111435","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T04:26:29Z","timestamp":1761711989000},"page":"1435","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Dual Inhibitory Potential of Conessine Against HIV and SARS-CoV-2: Structure-Guided Molecular Docking Analysis of Critical Viral Targets"],"prefix":"10.3390","volume":"17","author":[{"given":"Ali Hazim","family":"Abdulkareem","sequence":"first","affiliation":[{"name":"Department of Biotechnology, College of Science, University of Anbar, Ramadi 31001, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meena Thaar","family":"Alani","sequence":"additional","affiliation":[{"name":"College of Dentistry, University of Anbar, Ramadi 31001, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9194-719X","authenticated-orcid":false,"given":"Sameer Ahmed","family":"Awad","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratories Techniques, College of Health and Medical Technology, University of Al Maarif, Al Anbar 31001, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Safaa Abed Latef","family":"Al-Meani","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Science, University of Anbar, Ramadi 31001, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2831-9246","authenticated-orcid":false,"given":"Mohammed Mukhles","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Science, University of Anbar, Ramadi 31001, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5705-8866","authenticated-orcid":false,"given":"Elham Hazeim","family":"Abdulkareem","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, College of Dentistry, University of Anbar, Ramadi 31001, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaid Mustafa","family":"Khaleel","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Science, University of Anbar, Ramadi 31001, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e24","DOI":"10.1016\/S2352-3018(20)30305-2","article-title":"HIV infection and COVID-19 death: A population-based cohort analysis of UK primary care data and linked national death registrations within the OpenSAFELY platform","volume":"8","author":"Bhaskaran","year":"2021","journal-title":"Lancet HIV"},{"key":"ref_2","unstructured":"World Health Organization (2024). 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