Assessing Potential Inhibitors for SARS-CoV-2 Main Protease from Available Drugs using Free Energy Perturbation Simulations

Ngo, Son Tung; Nguyen, Hung Minh; Hường, Lê Thị Thu; Quân, Phạm Minh; Truong, Vi Khanh; Tung, Nguyen Thanh; Vu, Van V.

doi:10.26434/chemrxiv.12771068.v1

Cited by 7 publications

(15 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Table S4) or it may argue that the vdW interactions control the binding process of inhibitors to the protease. It is in good agreement with the previous outcomes 16,18 and obtained results via MM-PBSA and perturbation calculations below. Furthermore, the negative value implies that the hydrophobic interactions between inhibitors and the SARS-CoV-2 Mpro are strong as mentioned as conclusion about the superior of vdW term above.…”

Section: Molecular Dynamics Simulationssupporting

confidence: 93%

“…In particular, FEP simulations determined the ligand-binding free energy of 11 inhibitors to SARS-CoV-2 Mpro with high accuracy, = 0.94 ± 0.04. 18 In a different study, perturbation simulations also formed a Pearson correlation = 0.54, when 15 complexes were considered. 79 Therefore, in this work, we benchmarked the FEP performance on a larger set from multi-sources would probably provide a clarification for the accomplishment of this approach.…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 98%

“…Because the molecular docking simulations often use many constraints/approximations to accelerate the calculation speed, the results often need to be refined using more accurate protocols. 17,18 In this context, because Vina formed the most suitable binding affinity and pose as discussed above, we have chosen the docking structures provided by this approach as initial structures for simulating via SMD/MD techniques. The ligand-binding free energy calculation methods were thus carried out.…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

“…In recent reports, 18,79 the FEP simulations successfully determined the ligand-binding free energy as known as the most accurate free energy methods. 23,81 However, although the perturbation results correlate with the respective experiments, 18,79 the Pearson coefficient diffused in a large range from 0.54 to 0.94. In particular, FEP simulations determined the ligand-binding free energy of 11 inhibitors to SARS-CoV-2 Mpro with high accuracy, = 0.94 ± 0.04.…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

“…12,13 In particular, the SARS-CoV-2 Mpro sunders 11 polyproteins to polypeptides, which are served for replication and encapsulate a new virus. 12 Several probes in both computational and experimental studies were executed chasing the scheme and acquired preliminary results, [14][15][16][17][18] however, as mentioned above, it was a controversial decision 8 and moreover, an effective drug inhibiting SARS-CoV-2 Mpro is still unattainable.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

A Benchmark of Popular Free Energy Approaches Revealing the Inhibitors Binding to SARS-CoV2 Mpro

Ngo

Tam²,

Quân³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

COVID-19 pandemic has killed millions of people worldwide since its outbreak in Dec 2019. The pandemic is caused by the SARS-CoV-2 virus whose main protease (Mpro) is a promising drug target since it plays a key role in viral proliferation and replication. Currently, designing an effective therapy is an urgent task, which requires accurately estimating ligand-binding free energy to the SARS-CoV-2 Mpro. However, it should be noted that the accuracy of a free energy method probably depends on the protein target. A highly accurate approach for some targets may fail to produce a reasonable correlation with experiment when a novel enzyme is considered as a drug target. Therefore, in this context, the ligand-binding affinity to SARS-CoV-2 Mpro was calculated via various approaches. The Autodock Vina (Vina) and Autodock4 (AD4) packages were manipulated to preliminary investigate the ligand-binding affinity and pose to the SARS-CoV-2 Mpro. The binding free energy was then refined using the fast pulling of ligand (FPL), linear interaction energy (LIE), molecular mechanics-Poission Boltzmann surface area (MM-PBSA), and free energy perturbation (FEP) methods. The benchmark results indicated that for docking calculations, Vina is more accurate than AD4 and for free energy methods, FEP is the most accurate followed by LIE, FPL and MM-PBSA (FEP > LIE > FPL > MM-PBSA). Moreover, the binding mechanism was also revealed by atomistic simulations. The vdW interaction is the dominant factor. The residues Thr25, Thr26, His41, Ser46, Asn142, Gly143, Cys145, Glu166, and Gln189 are essential elements affecting on the binding process. Furthermore, the Ser46 and related residues probably are important elements affecting the enlarge/dwindle of the SARS-CoV-2 Mpro binding cleft. The benchmark probably guide for further investigations using computational approaches.

show abstract

Section: Molecular Dynamics Simulationssupporting

confidence: 93%

Section: Molecular Dynamics Simulationsmentioning

confidence: 98%

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A Benchmark of Popular Free Energy Approaches Revealing the Inhibitors Binding to SARS-CoV2 Mpro

Ngo

Tam²,

Quân³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Cytotoxic and α‐Glucosidase Inhibitory Xanthones from Garcinia mckeaniana Leaves and Molecular Docking Study

Thu

Minh²,

Van

et al. 2021

Chemistry & Biodiversity

View full text Add to dashboard Cite

A new racemic xanthone, garmckeanin A (1), and eight known analogs 2–9 were isolated from the ethyl acetate (AcOEt) extract of the Vietnamese Garcinia mckeaniana leaves. Their structures were determined by MS and NMR spectral analyses and compared with the literature. The AcOEt extract showed good cytotoxicity against cancer cell lines KB, Lu, Hep‐G2 and MCF7, with IC50 values of 5.40–8.76 μg/mL, and it also possessed α‐glucosidase inhibitory activity, with an IC50 value of 9.17 μg/mL. Garmckeanin A (1) exhibited inhibition of all cancer cell lines, with an IC50 value of 7.3–0.9 μM. Allanxanthone C (5) successfully controlled KB growth, with an IC50 value of 0.54 μM, higher than that of the positive control, ellipticine (IC50 1.22 μM). Norathyriol (8) was a promising α‐glucosidase inhibitor, with an IC50 value of 0.07 μM, much higher than that of the positive control, acarbose (IC50 161.0 μM). The interactions of the potential α‐glucosidase inhibitors with the C‐ and N‐terminal domains of human intestinal α‐glucosidase were also investigated by molecular docking study. The results indicated that bannaxanthone D (2), garcinone E (4), bannaxanthone E (6), and norathyriol (8) exhibit higher binding affinity to the C‐terminal than to the N‐terminal domain through essential residues in the active sites. In particular, compound 8 could be assumed to be the most potent mixed inhibitor.

show abstract

Structural insights into the substrate‐binding site of main protease for the structure‐based COVID‐19 drug discovery

2022

View full text Add to dashboard Cite

An attractive drug target to combat COVID‐19 is the main protease (Mpro) because of its key role in the viral life cycle by processing the polyproteins translated from the viral RNA. Studying the crystal structures of the protease is important to enhance our understanding of its mechanism of action at the atomic‐level resolution, and consequently may provide crucial structural insights for structure‐based drug discovery. In the current study, we report a comparative structural analysis of the Mpro substrate binding site for both apo and holo forms to identify key interacting residues and conserved water molecules during the ligand‐binding process. It is shown that in addition to the catalytic dyad residues (His41 and Cys145), the oxyanion hole residues (Asn142–Ser144) and residues His164–Glu166 form essential parts of the substrate‐binding pocket of the protease in the binding process. Furthermore, we address the issue of the substrate‐binding pocket flexibility and show that two adjacent loops in the Mpro structures (residues Thr45–Met49 and Arg188–Ala191) with high flexibility can regulate the binding cavity’ accessibility for different ligand sizes. Moreover, we discuss in detail the various structural and functional roles of several important conserved and mobile water molecules within and around the binding site in the proper enzymatic function of Mpro. We also present a new docking protocol in the framework of the ensemble docking strategy. The performance of the docking protocol has been evaluated in predicting ligand binding pose and affinity ranking for two popular docking programs; AutoDock4 and AutoDock Vina. Our docking results suggest that the top‐ranked poses of the most populated clusters obtained by AutoDock Vina are the most important representative docking runs that show a very good performance in estimating experimental binding poses and affinity ranking.

show abstract

Assessing Potential Inhibitors for SARS-CoV-2 Main Protease from Available Drugs using Free Energy Perturbation Simulations

Cited by 7 publications

References 14 publications

A Benchmark of Popular Free Energy Approaches Revealing the Inhibitors Binding to SARS-CoV2 Mpro

A Benchmark of Popular Free Energy Approaches Revealing the Inhibitors Binding to SARS-CoV2 Mpro

Cytotoxic and α‐Glucosidase Inhibitory Xanthones from Garcinia mckeaniana Leaves and Molecular Docking Study

Structural insights into the substrate‐binding site of main protease for the structure‐based COVID‐19 drug discovery

Contact Info

Product

Resources

About