MM-GB(PB)SA Calculations of Protein-Ligand Binding Free Energies

Hayes, Joseph M.; Archontis, Georgios

doi:10.5772/37107

Cited by 33 publications

(8 citation statements)

References 78 publications

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“…where H MM is the bonded and Lennard-Jones energy terms; G solv is the polar contribution of solvation energy and nonpolar contribution to the solvation energy; T is the temperature; and ΔS conf corresponds to the conformational entropy (Hayes and Archontis, 2012). Both H MM and G solv were calculated using AMBER 18 program with the generalized Born implicit solvent model (Götz et al, 2012;Song et al, 2019).…”

Section: Free Energy Calculationmentioning

confidence: 99%

In Silico Study of Coumarins and Quinolines Derivatives as Potent Inhibitors of SARS-CoV-2 Main Protease

et al. 2021

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The pandemic that started in Wuhan (China) in 2019 has caused a large number of deaths, and infected people around the world due to the absence of effective therapy against coronavirus 2 of the severe acute respiratory syndrome (SARS-CoV-2). Viral maturation requires the activity of the main viral protease (Mpro), so its inhibition stops the progress of the disease. To evaluate possible inhibitors, a computational model of the SARS-CoV-2 enzyme Mpro was constructed in complex with 26 synthetic ligands derived from coumarins and quinolines. Analysis of simulations of molecular dynamics and molecular docking of the models show a high affinity for the enzyme (∆Ebinding between −5.1 and 7.1 kcal mol−1). The six compounds with the highest affinity show Kd between 6.26 × 10–6 and 17.2 × 10–6, with binding affinity between −20 and −25 kcal mol−1, with ligand efficiency less than 0.3 associated with possible inhibitory candidates. In addition to the high affinity of these compounds for SARS-CoV-2 Mpro, low toxicity is expected considering the Lipinski, Veber and Pfizer rules. Therefore, this novel study provides candidate inhibitors that would allow experimental studies which can lead to the development of new treatments for SARS-CoV-2.

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Section: Free Energy Calculationmentioning

confidence: 99%

In Silico Study of Coumarins and Quinolines Derivatives as Potent Inhibitors of SARS-CoV-2 Main Protease

et al. 2021

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“…where E MM is the bonded and Lennard-Jones energy terms, G solv is the polar contribution of solvation energy and non-polar contribution to the solvation energy, T is the temperature, and ΔS conf corresponds to the conformational entropy 50 . Both E MM and G solv were calculated using the NAMD software with the generalized Born implicit solvent model 51,52 .…”

Section: Free Energy Calculationmentioning

confidence: 99%

Theoretical and Experimental Study of New Dihydroorotate Dehydrogenase and Tryparedoxin Peroxidase Inhibitors: One More Step in the Study of Leishmaniasis Infection

Espinosa-Saez

Robledo

Pineda

et al. 2021

Preprint

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In this study, the viability of new dihydroorotate dehydrogenase and tryparedoxin peroxidase inhibitors is reported. In vitro antileishmanial activity was evaluated using a Leishmania (V) panamensis strain, and the cytotoxicity of the compounds was assessed using U-937 cells. The in vivo therapeutic response was evaluated in golden hamsters (Mesocricetus auratus) experimentally infected with L. (V) panamensis and treated with a 1% topical formulation of compounds 4a–f. On the other hand, in silico studies considering the synthesized compounds were also carried out. All of the compounds showed promising in vitro activity, with mean EC50 effective concentration values ranging from 3.8 µM to 19.3 µM. Likewise, treatment with compounds 4a–f produced improvement in most of the hamsters and cured some; in particular, those treated with compounds 4b, 4c, 4d, and 4f reacted the best. Molecular dynamics (MD) simulations, computational docking, and MM/GBSA studies indicate the promising bioavailability and absorption characteristics of the studied compounds, which are expected to be orally active. In addition, the studied 2-arylquinolines are absorbable at the blood–brain barrier, but not in the gastrointestinal tract. Finally, ADMET properties suggest that these molecules can be safely used as leishmaniasis inhibitors.

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“…The post-MD coordinates and trajectories obtained were analysed using the integrated CPPTRAJ and PTRJ modules containing in the AMBER 18 package (Genheden & Ryde, 2015;Hayes & Archontis, 2012). Subsequently, some post-MD analyses including root mean square fluctuation (RMSF), the radius of gyration (RoG), dynamic cross-correlation matrix (DCCM), definition secondary structure protein (DSSP), others used to investigate the molecular systems in this study.…”

Section: Simulationsmentioning

confidence: 99%

“…The surface tension constant, c, was set at 0.0072 kcal/mol Å 2 . The contribution of each residue to the total BFE obtained at the predicted active site by carrying out per-residue energy decomposition (PRED) at the atomic level using MM/GBSA method in AMBER 18 (Genheden & Ryde, 2015;Hayes & Archontis, 2012).…”

Section: Thermodynamic Calculationsmentioning

confidence: 99%

Weak spots inhibition in the Mycobacterium tuberculosis antigen 85C target for antitubercular drug design through selective irreversible covalent inhibitor-SER124

Adewumi

El-Rashedy

Soremekun

et al. 2020

Journal of Biomolecular Structure and Dynamics

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Mycobacterium tuberculosis (Mtb) encoded secreted antigen 85 enzymes (Ag85A/Ag85B/Ag85C) play that critical roles in the virulence, survival and drug-resistant TB of the pathogen. Ag85 proteins are potential antitubercular drug targets because they are essential in the catalytic synthesis of trehalose moieties and mycolic acid attachment to the Mtb cell wall. Recently, experimental protocols led to the discovery of a selective covalent Ag85 inhibitor, b-isomer monocyclic enolphosphorus Cycliphostin (CyC 8b) compound, which targets the Ag85 serine 124 to exhibit a promising therapeutic activity. For the first time, our study unravelled the structural features among Mtb Ag85C homologs and motions and dynamics of Ag85C when the CyC 8b bound covalently and in open model conformations to the protein using bioinformatics tools and integrated Molecular dynamics simulations. Comparative Ag85C sequence analysis revealed conserved regions; 70% active site, 90% Adeniyi loop L1 and 50% loop L2, which acts as a switch between open and closed conformations. The average C-a atoms RMSD (2.05 Å) and RMSF (0.9 Å) revealed instability and high induced flexibility in the CyC 8b covalent-bound compared to the apo and open model systems, which displayed more stability and lower fluctuations. DSSP showed structural transitions of a-helices to bend and loops to 3 10-helices in the bound systems. SASA of CyC 8b covalent bound showed active site hydrophobic residues exposure to huge solvent. Therefore, these findings present the potential opportunity hotspots in Ag85C protein that would aid the structure-based design of novel chemical entities capable of resulting in potent antitubercular drugs.

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MM-GB(PB)SA Calculations of Protein-Ligand Binding Free Energies

Cited by 33 publications

References 78 publications

In Silico Study of Coumarins and Quinolines Derivatives as Potent Inhibitors of SARS-CoV-2 Main Protease

In Silico Study of Coumarins and Quinolines Derivatives as Potent Inhibitors of SARS-CoV-2 Main Protease

Theoretical and Experimental Study of New Dihydroorotate Dehydrogenase and Tryparedoxin Peroxidase Inhibitors: One More Step in the Study of Leishmaniasis Infection

Weak spots inhibition in the Mycobacterium tuberculosis antigen 85C target for antitubercular drug design through selective irreversible covalent inhibitor-SER124

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