*Article* **In Silico and In Vitro Studies of** *Alchemilla viridiflora* **Rothm—Polyphenols' Potential for Inhibition of SARS-CoV-2 Internalization**

**Relja Suruˇci´c 1,\*, Jelena Radovi´c Selgrad 2, Tatjana Kundakovi´c-Vasovi´c 2, Biljana Lazovi´c 3, Maja Travar 4, Ljiljana Suruˇci´c <sup>5</sup> and Ranko Škrbi´c 6,\***


**Abstract:** Since the outbreak of the COVID-19 pandemic, it has been obvious that virus infection poses a serious threat to human health on a global scale. Certain plants, particularly those rich in polyphenols, have been found to be effective antiviral agents. The effectiveness of *Alchemilla viridiflora* Rothm. (Rosaceae) methanol extract to prevent contact between virus spike (*S*)-glycoprotein and angiotensinconverting enzyme 2 (ACE2) and neuropilin-1 (NRP1) receptors was investigated. In vitro results revealed that the tested samples inhibited 50% of virus-receptor binding interactions in doses of 0.18 and 0.22 mg/mL for NRP1 and ACE2, respectively. Molecular docking studies revealed that the compounds from *A. viridiflora* ellagitannins class had a higher affinity for binding with S-glycoprotein whilst flavonoid compounds more significantly interacted with the NRP1 receptor. Quercetin 3-(6"-ferulylglucoside) and pentagalloylglucose were two compounds with the highest exhibited interfering potential for selected target receptors, with binding energies of −8.035 (S-glycoprotein) and −7.685 kcal/mol (NRP1), respectively. Furthermore, computational studies on other SARS-CoV-2 strains resulting from mutations in the original wild strain (V483A, N501Y-K417N-E484K, N501Y, N439K, L452R-T478K, K417N, G476S, F456L, E484K) revealed that virus internalization activity was maintained, but with different single compound contributions.

**Keywords:** *Alchemilla viridiflora* Rothm.; polyphenols; SARS-CoV-2; COVID-19; spike glycoprotein; neuropilin-1; in vitro; in silico
