Assessing potential inhibitors of SARS-CoV-2 main protease from available drugs using free energy perturbation simulations

Ngo, Son Tung; Nguyen, Hung Minh; Hường, Lê Thị Thu; Quan, Pham Minh; Truong, Vi Khanh; Tùng, Nguyễn Thanh; Vu, Van V.

doi:10.1039/d0ra07352k

Cited by 26 publications

(28 citation statements)

References 35 publications

(67 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Table S4 ) or it may be argued 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 γ implies that the hydrophobic interactions between inhibitors and SARS-CoV-2 Mpro are strong as mentioned in the conclusion about the superiority of the above vdW term.…”

Section: Resultssupporting

confidence: 93%

“…Furthermore, the obtained results by λ-alteration simulations also revealed the binding process of the SARS-CoV-2 Mpro inhibitor. The vdW interaction is dominant in the binding process of ligands to Mpro, which is in good agreement with the previous observations 16 , 18 because the average values of Δ G cou and Δ G vdW are −2.82 ± 0.83 and −7.05 ± 0.49 kcal mol –1 , respectively.…”

Section: Resultssupporting

confidence: 92%

“…In particular, FEP simulations determined the ligand-binding free energy of 11 inhibitors to SARS-CoV-2 Mpro with high accuracy, R FEP = 0.94 ± 0.04. 18 In a different study, perturbation simulations also formed a Pearson correlation R FEP = 0.54 when 15 complexes were considered. 84 Therefore, in this work, we benchmarked the FEP performance on a larger set from multi-sources, which would probably provide a clarification for the accomplishment of this approach.…”

Section: Resultsmentioning

confidence: 98%

“…12 , 13 In particular, SARS-CoV-2 Mpro splits 11 polyproteins into polypeptides, which are used for replication and to encapsulate a new virus. 12 Several probes in both computational and experimental studies were used to develop an effective therapy and preliminary results were acquired; 14 − 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 3 more Smart Citations

Benchmark of Popular Free Energy Approaches Revealing the Inhibitors Binding to SARS-CoV-2 Mpro

Ngo

Tam

Quan

et al. 2021

J. Chem. Inf. Model.

Self Cite

118

View full text Add to dashboard Cite

The COVID-19 pandemic has killed millions of people worldwide since its outbreak in December 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, developing an effective therapy is an urgent task, which requires accurately estimating the ligand-binding free energy to 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 the 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 molecular docking approach was manipulated using Autodock Vina (Vina) and Autodock4 (AD4) protocols to preliminarily investigate the ligand-binding affinity and pose to SARS-CoV-2 Mpro. The binding free energy was then refined using the fast pulling of ligand (FPL), linear interaction energy (LIE), molecular mechanics-Poisson–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 method, followed by LIE, FPL, and MM-PBSA (FEP > LIE ≈ FPL > MM-PBSA). Moreover, atomistic simulations revealed that the van der Waals interaction is the dominant factor. The residues Thr26 , His41 , Ser46 , Asn142 , Gly143 , Cys145 , His164 , Glu166 , and Gln189 are essential elements affecting the binding process. Our benchmark provides guidelines for further investigations using computational approaches.

show abstract

Section: Resultssupporting

confidence: 93%

Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Benchmark of Popular Free Energy Approaches Revealing the Inhibitors Binding to SARS-CoV-2 Mpro

Ngo

Tam

Quan

et al. 2021

J. Chem. Inf. Model.

Self Cite

118

View full text Add to dashboard Cite

show abstract

“…The Glu-166 residue is in the S1 pocket, whereas Met-165 and Val-186 are in the S2 pocket and Pro-168 and Gln-189 are located in the S4 site [ 49 ]. As compared to other receptor sites in the SARS-Cov-2 proteins, the Mpro site is comparatively flexible and can accommodate a wide variety of ligands, including peptides and small molecules [ 68 ]. This characteristic is important as it makes the docking critical because many compounds could have appreciable docking scores at this site.…”

Section: Discussionmentioning

confidence: 99%

The interaction of the bioflavonoids with five SARS-CoV-2 proteins targets: An in silico study

Mishra

Bhadane

Panigrahi³

et al. 2021

Computers in Biology and Medicine

View full text Add to dashboard Cite

Flavonoids have been shown to have antioxidant, anti-inflammatory, anti-proliferative, antibacterial and antiviral efficacy. Therefore, in this study, we choose 85 flavonoid compounds and screened them to determine their in-silico interaction with protein targets crucial for SARS-CoV-2 infection. The five important targets chosen were the main protease (Mpro), Spike receptor binding domain (Spike-RBD), RNA - dependent RNA polymerase (RdRp or Nsp12), non-structural protein 15 (Nsp15) of SARS-CoV-2 and the host angiotensin converting enzyme-2 (ACE-2) spike-RBD binding domain. The compounds were initially docked at the selected sites and further evaluated for binding free energy using the molecular mechanics/generalized Born surface area (MMGBSA) method. The three compounds with the best binding scores were subjected to molecular dynamics (MD) simulations. The compound, tribuloside, had a high average binding free energy of -86.99 and -88.98 kcal/mol for Mpro and Nsp12, respectively. The compound, legalon, had an average binding free energy of -59.02 kcal/mol at the ACE2 spike-RBD binding site. The compound, isosilybin, had an average free binding energy of -63.06 kcal/mol for the Spike-RBD protein. Overall, our results suggest that the tribuloside, legalon and isosilybin compounds should be evaluated in future studies to determine their efficacy to inhibit SARS-CoV-2 infectivity.

show abstract

Structure–activity relationship and in silico development of c‐Met kinase inhibitors

Ghosh

Cho

2022

Bulletin Korean Chem Soc

View full text Add to dashboard Cite

Overexpression and concomitant drug resistance of c-Met kinase are strongly associated with poor prognosis in gastric carcinoma. This needs the further development of existing lead compounds against c-Met. Herein, we conducted molecular modeling studies of 4-phenoxypyridine derivatives as c-Met kinase inhibitors using docking, molecular dynamics (MD), and binding energy estimation to examine receptor-ligand interaction, complex stability, and binding affinity. We developed statistically significant three-dimensional structureactivity relationship models (3D-QSAR) to correlate the physicochemical characteristics of the inhibitors with their biological activities. The field effects of the chemical descriptors were determined as contour polyhedrons and emphasized as SAR. Thirty new compounds were designed according to the SAR scheme, and their activities were predicted using the 3D-QSAR model. The designed compounds with higher predicted pIC 50 values than the most active compounds in the dataset were subjected to absolute binding free-energy evaluation by free energy perturbation (FEP) method.

show abstract

Assessing potential inhibitors of SARS-CoV-2 main protease from available drugs using free energy perturbation simulations

Abstract: Free Energy Pertubation (FEP) can be used to accurately predict the binding affinity of a ligand to the main protease (Mpro) of the novel coronavirus SARS-CoV-2.

Cited by 26 publications

References 35 publications

Benchmark of Popular Free Energy Approaches Revealing the Inhibitors Binding to SARS-CoV-2 Mpro

Benchmark of Popular Free Energy Approaches Revealing the Inhibitors Binding to SARS-CoV-2 Mpro

The interaction of the bioflavonoids with five SARS-CoV-2 proteins targets: An in silico study

Structure–activity relationship and in silico development of c‐Met kinase inhibitors

Contact Info

Product

Resources

About