Integrated Approach to Structure-Based Enzymatic Drug Design: Molecular Modeling, Spectroscopy, and Experimental Bioactivity

Honarparvar, Bahareh; Govender, Thavendran; Maguire, Glenn E. M.; Soliman, Mahmoud E. S.; Kruger, Hendrik G.

doi:10.1021/cr300314q

Cited by 112 publications

(70 citation statements)

References 728 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A density functional theory (DFT) geometry optimization with the Gaussian09 program package [22] employing the B3LYP (Becke three parameters Lee-Yang-Parr exchange correlation functional, which combines the hybrid exchange functional of Becke [23] with the gradient-correlation functional of Lee, Yang and Parr [24] and the 6-311G++(d,p) basis set were performed in gas phase). No solvent corrections were made with these calculations as it was reported that gas phase calculations frequently correspond quite well with crystal structures [25]. Starting geometries were taken from X-ray refined data.…”

Section: X-ray Structural Study and Theoretical Calculationsmentioning

confidence: 99%

Synthesis, Crystal Structure and DFT Studies of 1,3-Dimethyl-5-propionylpyrimidine-2,4,6(1H,3H,5H)-trione

et al. 2017

View full text Add to dashboard Cite

Novel 1,3-Dimethyl-5-propionylpyrimidine-2,4,6(1H,3H,5H)-trione was synthesized and recrystallized from ethanol. The compound was characterized by 1 H NMR, 13 C NMR in CDCl 3 , DMSO-d 6 and acetone-d 6 , elemental analysis and X-ray diffraction. The NMR data observed that the title compound exists in the enol tautomer rather than keto, and it stabilized by strong H-bond as observed form the NMR data at different temperatures. Theoretical calculations (DFT) were carried out using Gaussian09 program package and B3LYP correlation function. Full geometry optimization of the keto and enol forms were carried out using 6-311G++(d,p) basis set. The structure and energy of the transition state between these two tautomers were calculated. The frontier orbital energy and atomic net atomic charges of the tautomers were presented. The experimental results of the title compound have been compared with the theoretical results and it was found that the experimental data are in a good agreement with the calculated values. The transition state calculations also support the stability of enol form compared to keto form at room temperature.

show abstract

Section: X-ray Structural Study and Theoretical Calculationsmentioning

confidence: 99%

Synthesis, Crystal Structure and DFT Studies of 1,3-Dimethyl-5-propionylpyrimidine-2,4,6(1H,3H,5H)-trione

et al. 2017

View full text Add to dashboard Cite

show abstract

“…When the ligand binding site is already known, MD can be used to generate ensembles of receptor conformations against which site-directed docking can be performed via the 'relaxed complex' scheme [103]. This paradigm of coupling protein dynamics to HTVS through MD is being widely used [104,105]. A relatively new application of MD in drug discovery is for allosteric binding site identification [106].…”

Section: Conformational Ensembles and MD Simulationsmentioning

confidence: 99%

Computational allosteric ligand binding site identification on Ras proteins

McCarthy

Prakash

Gorfe

2016

ABBS

View full text Add to dashboard Cite

A number of computational techniques have been proposed to expedite the process of allosteric ligand binding site identification in inherently flexible and hence challenging drug targets. Some of these techniques have been instrumental in the discovery of allosteric ligand binding sites on Ras proteins, a group of elusive anticancer drug targets. This review provides an overview of these techniques and their application to Ras proteins. A summary of molecular docking and binding site identification is provided first, followed by a more detailed discussion of two specific techniques for binding site identification in ensembles of Ras conformations generated by molecular simulations.

show abstract

“…All computations were performed using the Gaussian 09 software suite [19]. The geometrical optimizations were performed in the gas phase without solvent corrections because it was reported that gas phase calculations frequently correspond quite well with crystal structures [20].…”

Section: Methodsmentioning

confidence: 99%

A Study of the Crystal Structure and Hydrogen Bonding of 3-Trifluoroacetyloxime Substituted 7-Acetamido-2-aryl-5-bromoindoles

Mphahlele

2018

Crystals

View full text Add to dashboard Cite

Abstract:The 7-acetyl-2-aryl-5-bromo-3-(trifluoroacetyl)indoles 1a-d were reacted with hydroxylamine hydrochloride (2.2 equiv.) in the presence of pyridine in ethanol under reflux to afford the corresponding diketo oxime derivatives 2a-d.Beckmann rearrangement of the latter with trifluoroacetic acid under reflux afforded the corresponding 7-acetamido-2-aryl-5-bromo-3-(trifluoroacetyloxime)indoles 3a-d. The structures of the prepared compounds were characterized using a combination of NMR ( 1 H & 13 C), IR, and mass spectrometric techniques. The molecular structure of the 3-trifluoroacetyloxime substituted 7-acetamido-2-aryl-5-bromoindoles was unambiguously confirmed by the single crystal X-ray diffraction data of 3d. Structural studies of 3d in the solid state by X-ray crystallography provided evidence of hydrogen bonding networks and π-stacking of the indole moiety. Compound 3d was crystallized in the trigonal space group R-3:H with unit cell dimensions a = 25.1614(13), b = 25.1614(13), c = 17.3032(9) Å, α = β = 90 • , γ = 120 • , V = 9486.9(11) Å 3 , Z = 6. The density functional theory (DFT) structural parameters (bond lengths, bond angles, and torsion angles) of the optimized geometry calculated using the B3LYP/6-311G basis set were found to compare favourably with those of the X-ray crystal structure.

show abstract

Integrated Approach to Structure-Based Enzymatic Drug Design: Molecular Modeling, Spectroscopy, and Experimental Bioactivity

Cited by 112 publications

References 728 publications

Synthesis, Crystal Structure and DFT Studies of 1,3-Dimethyl-5-propionylpyrimidine-2,4,6(1H,3H,5H)-trione

Synthesis, Crystal Structure and DFT Studies of 1,3-Dimethyl-5-propionylpyrimidine-2,4,6(1H,3H,5H)-trione

Computational allosteric ligand binding site identification on Ras proteins

A Study of the Crystal Structure and Hydrogen Bonding of 3-Trifluoroacetyloxime Substituted 7-Acetamido-2-aryl-5-bromoindoles

Contact Info

Product

Resources

About