IN SILICO STUDY OF SOME FLAVONOID COMPOUNDS AGAINST ACE-2 RECEPTORS AS ANTI- COVID-19 Original Article IDA MUSFIROH 1* , OKTAVIA SABETTA SIGALINGGING 1 , CECEP SUHANDI 1,2 , NUR KUSAIRA KHAIRUL IKRAM 3 , SANDRA MEGANTARA 1 , MUCHTARIDI MUCHTARIDI 1* 1 Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, West Java, Indonesia. 2 Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Padjadjaran, West Java, Indonesia. 3 Institute of Biological Sciences, Faculty of Science, Universiti Malaya, 50603, Kuala Lumpur, Malaysia * Corresponding author: Ida Musfiroh; * Email: ida.musfiroh@unpad.ac.id Received: 17 Apr 2023, Revised and Accepted: 19 May 2023 ABSTRACT Objective: The coronavirus disease 2019 (COVID-19) pandemic has become a global concern today. As a receptor that plays an important role in viral entry, inhibition of angiotensin-converting enzyme-2 (ACE-2) activity could prevent severe acute respiratory syndrome coronavirus-2 (SARS- CoV-2) infection. Quercetin is one of the flavonoid compounds reported to have activity as an ACE-2 inhibitor via interaction with the hydroxyl group at ring B positions 3' and 4'. The aims of this research to analyze the binding interaction of some flavonoid compounds into ACE-2 receptor to predict their activity as an anticovid-19. Methods: An in silico approach via molecular docking simulations was conducted, and the selection of potential compounds was based on Lipinski's rules, prediction of absorption, distribution, metabolism, and toxicity (ADMET). Results: The results showed that nepetin was the most potent compound, with a bond energy of-4.71 kcal/mol and an inhibition constant of 355.62 µM. The compound is bound to amino acid residues Asp30, His34, Glu35, and Thr27, which are important amino acid residues of the ACE-2 receptor. Conclusion: The nepetin compound complies with all Lipinski rules and has a better ADMET profile compared to other compounds. Keywords: ACE-2, COVID-19, Flavonoid, In silico © 2023 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/) DOI: https://dx.doi.org/10.22159/ijap.2023v15i4.48109. Journal homepage: https://innovareacademics.in/journals/index.php/ijap INTRODUCTION Since the first case in Wuhan, cases of Coronavirus Disease-19 (COVID-19) have been increasing every day. Based on data from World meter, as of May 10, 2021, it was reported that the number of positive cases of COVID-19 and mortality worldwide reached 158,974,260 and 3,306,830, respectively (1). In Indonesia, the number of positive cases of COVID-19 has reached 1,713,684 with 47,012 deaths (case fatality rate/CFR = 2.7%) [1]. COVID-19 is caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), which is transmitted from human to human through droplets released by an infected person’s coughs or sneezes, which are inhaled or through contact with contaminated objects in the vicinity of the infected person [2]. Clinical manifestations of COVID-19 usually appear within 3-14 d after exposure. Common symptoms of COVID-19 include fever, cough, and shortness of breath. However, a person exposed to SARS-CoV-2 may not show any symptoms (asymptomatic) and can still transmit the virus to others [3]. Various types of synthetic drugs have been used as therapy in patients with COVID-19 to reduce the case fatality rate (CFR), one of which is chloroquine. However, research has reported that the side effects are greater than the effectiveness [4]. Therefore, further research is needed to find active compounds that can be used in COVID-19 therapy. In the search for active compounds, a phytochemical study was carried out by screening compounds that have the potential for COVID-19. Flavonoids (fig. 1) are compounds that can be found in many plants and have bioactivity that is beneficial to health, such as anti-inflammatory, antioxidant, antimicrobial, and antiviral [5]. This bioactive compound has the potential to be developed as an anti- COVID-19 drug by considering its mechanism of action as an inhibitor of the Angiotensin Converting Enzyme-2 (ACE-2) receptor as well as chloroquine. Fig. 1: Structure of flavonoids [6] ACE-2 is an integral type 1 membrane protein and a functional receptor for SARS-CoV-2, playing an important role in virus transmission into alveolar cells [7, 8]. Inhibition of ACE-2 activity could be promising in preventing SARS-CoV-2 infection due to its role in viral entry. Quercetin is one of the flavonoid compounds reported to have activity as an ACE-2 inhibitor, with two hydroxyl groups in ring B (positions 3' and 4') of the quercetin structure (fig. 2) playing a role in the inhibition [9]. Therefore, it is postulated that other flavonoid compounds with structures similar to quercetin could provide similar activity. Fig. 2: Quercetin [9] Delphinidine, eriocitrin, eriodictyol, gossypetin, hyperoside, luteolin, monoxerutin, myricetin, nepetin, nepitrin, orientin, rhamnetin, International Journal of Applied Pharmaceutics ISSN- 0975-7058 Vol 15, Issue 4, 2023