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Potential SARS-CoV-2 3CLpro inhibitors from chromene, flavonoid and hydroxamic acid compound based on FRET assay, docking and pharmacophore studies.

ABSTRACT: This present study reports some natural products and one hydroxamic acid synthetic compound which were previously reported as matrix metalloproteinase-9 (MMP-9) inhibitors to be evaluated for their inhibition toward severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) 3-chymotrypsin-like protease (3CLpro). This enzyme is one of the proteins responsible for this coronaviral replication. Two herbal methanolic extracts i.e., Averrhoa carambola leaves and Ageratum conyzoides aerial part demonstrate >50% inhibition at 1000 µg/mL. Interestingly, apigenin, one of flavonoids, demonstrates 92% inhibition at 250 µg/mL (925 µM) as well as hydroxamic acid compound, N-isobutyl-N-(4-methoxyphenylsulfonyl)glycyl hydroxamic acid (NNGH), which shows 69% inhibition at 100 µM. The in vitro results are supported by the docking studies revealing that the binding mode of both compounds is mainly by interacting with GLU166 residue in the hydrophobic pocket of the 3CLpro. Pharmacophore mapping further supported the results by confirming that the in vitro activities of both compounds are due to their pharmacophore features employing hydrogen bond acceptor (HBA), hydrogen bond donor (HBD) and hydrophobic. Gas Chromatography-Mass Spectrometry (GC-MS) analysis reported chromene compounds in Ageratum conyzoides aerial part methanolic extract are potential to be this enzyme inhibitor candidate. These all results reflect their potencies to be SARS-CoV-2 inhibitors through 3CLpro inhibition mechanism.

SUBMITTER: Hariono M

PROVIDER: S-EPMC8451405 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Among the biomedical efforts in response to the current coronavirus (COVID-19) pandemic, pharmacological strategies to reduce viral load in patients with severe forms of the disease are being studied intensively. One of the main drug target proteins proposed so far is the SARS-CoV-2 viral protease 3CLpro (also called Mpro), an essential component for viral replication. Ongoing ligand- and receptor-based computational screening efforts would be facilitated by an improved understanding of the electrostatic, hydrophobic, and steric features that characterize small-molecule inhibitors binding stably to 3CLpro and by an extended collection of known binders. Here, we present combined virtual screening, molecular dynamics (MD) simulation, machine learning, and in vitro experimental validation analyses, which have led to the identification of small-molecule inhibitors of 3CLpro with micromolar activity and to a pharmacophore model that describes functional chemical groups associated with the molecular recognition of ligands by the 3CLpro binding pocket. Experimentally validated inhibitors using a ligand activity assay include natural compounds with the available prior knowledge on safety and bioavailability properties, such as the natural compound rottlerin (IC50 = 37 μM) and synthetic compounds previously not characterized (e.g., compound CID 46897844, IC50 = 31 μM). In combination with the developed pharmacophore model, these and other confirmed 3CLpro inhibitors may provide a basis for further similarity-based screening in independent compound databases and structural design optimization efforts to identify 3CLpro ligands with improved potency and selectivity. Overall, this study suggests that the integration of virtual screening, MD simulations, and machine learning can facilitate 3CLpro-targeted small-molecule screening investigations. Different receptor-, ligand-, and machine learning-based screening strategies provided complementary information, helping to increase the number and diversity of the identified active compounds. Finally, the resulting pharmacophore model and experimentally validated small-molecule inhibitors for 3CLpro provide resources to support follow-up computational screening efforts for this drug target.

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Potential SARS-CoV-2 3CLpro inhibitors from chromene, flavonoid and hydroxamic acid compound based on FRET assay, docking and pharmacophore studies.

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