Chromone-embedded peptidomimetics and furopyrimidines as highly potent SARS-CoV-2 infection inhibitors: docking and MD simulation study

Abstract

Background: COVID-19 is a respiratory illness caused by SARS-CoV-2. Pharmaceutical companies aim to control virus spread through effective drugs. This study investigates chromone compound derivatives' ability to inhibit viral entry and prevent replication.

Method: This study investigated the inhibitory effect of chromone-embedded peptidomimetics and furopyrimidines on 7BZ5 from Severe Acute Respiratory Syndrome CoV-2, Homo sapiens, and 6LU7 from Bat SARS-like CoV using molecular docking. The crystal structure of these proteins was obtained from the Protein Data Bank, and the inhibition site was determined using ligand binding interaction options. The 3D structure was protonated and energetically minimised using MOE software. Chromone derivatives were designed in three dimensions, and their energy was minimised using MOE 2019. The molecular drug-likeness was calculated using SwissADME, Lipinski and Benigni-Bossa's rule, and toxicity was calculated using Toxtree v3.1.0 software. Compounds with pharmacological properties were selected for molecular docking, and interactions were assessed using MOE 2019. MD simulations of Mpro-ch-p complexes were performed to evaluate root mean square fluctuations (RMSF) and measure protein stability.

Result: The pharmacokinetic tests revealed that chromone derivatives of the peptidomimetic family have acceptable pharmacokinetic activity in the human body. Some compounds, such as Ch-p1, Ch-p2, Ch-p6, Ch-p7, Ch-p12, and Ch-p13, have pronounced medicinal properties. Molecular docking revealed high affinity for binding to SARS-CoV-2 protease. Ch-p7 had the highest binding energy, likely due to its inhibitory property. A 10 ns molecular dynamics study confirmed the stability of the protein-ligand complex, resulting in minimal fluctuations in the system's backbone. The MM-GBSA analysis revealed free energies of binding of - 19.54 kcal/mol.

Conclusions: The study investigated the inhibition of viral replication using chromone derivatives, finding high inhibitory effects in the peptidomimetic family compared to other studies.

Keywords: Chromone derivatives; Infection inhibitors; Main protease domain; Molecular docking; SARS-CoV-2; Spike receptor binding domain.

Fig. 1

The summarized steps in selecting, preparing, and molecular docking the compounds studied

Fig. 2

Interaction of Ch-p1, Ch-p6, Ch-p7, Ch-p12, and Ch-p13 with the SARS-CoV-2 spike receptor domain. A A benzene ring in Ch-p1 was bound to Arg403, and a carbonyl group was bound to Gln493. B Ch-p2 was bound to Lys417 via the benzene ring and to the amino acid Ser494 via the amino group. C Ch-p6 was bound to Lys417, Arg403, and Tyr453 in different positions via the carbonyl group. D Ch-p7 was bound to Leu455 via the benzene group and Lys417 via the CO group. Arg403 of SARS-CoV-2 was also bound to this compound. E Ch-p12 was bound to Leu455 via the benzene group and Arg403 via the CO group. F Ch-p13 was bound to Arg403 via two bonds and Gln493 and Lys417 via the CO group. The Arg403, Ala475, and Asn487 residues in this domain play an essential role in interacting with the human ACE2 receptor. The interaction of the ACE2 receptor with the RBD of SARS-CoV-2 is also mediated by amino acids Gln493 and Leu455. Chromone derivatives inhibit the binding of this domain to human ACE2 receptors. Therefore, the function of this protein is expected to be impaired if it does not bind to ACE2 receptors

Fig. 3

Interaction of Ch-p1, Ch-p6, Ch-p7, Ch-p12, and Ch-p13 with the Mpro of SARS-CoV-2. The Mpro of SARS-CoV-2 was inhibited by chromone derivatives binding to its primary amino acids (Phe140, His172, Gly143, His164, Glu166, Met165, Gln189, and Thr190). This site contains many essential amino acids at the active site of protomer A (Phe141, Asn142, Glu166, His163, and His 172), and inhibition of this site impairs proteolytic processing. The chromone derivatives bind to the amino acids of protomer A in the following order: Ch-p1 and Ch-p2 bind to Gln189 and Glu166, respectively. In addition, Gln189 binds to both Ch-p7 and Ch-p12. Thus, Gln189, Glu166, and His164 appear to play essential roles in the function of this protein. Among the interactions detected with the main SARS-CoV-2 protease, compound Ch-p12 had a greater tendency to inhibit protomer A, with an S-score of -8.7005

Fig. 4

NMA results include protein domain mobility diagrams, PDB and NMA B-factor diagrams, deformation diagrams for atomic fluctuations, eigenvalue diagrams, covariance matrix diagrams, elastic network diagrams and structural flexibility (RMSF). In addition, the interaction between the ligand and the protein is shown according to MD