QTAIM Application in Drug Development: Prediction of Relative Stability of Drug Polymorphs from Experimental Crystal Structures

2011 ◽  
Vol 115 (45) ◽  
pp. 12809-12817 ◽  
Author(s):  
Yuriy A. Abramov
Keyword(s):  
Drug Development ◽  
Crystal Structures ◽  
Relative Stability ◽  
Experimental Crystal

scholarly journals Validation of experimental molecular crystal structures with dispersion-corrected density functional theory calculations

2010 ◽  
Vol 66 (5) ◽  
pp. 544-558 ◽  
Author(s):  
Jacco van de Streek ◽  
Marcus A. Neumann
Keyword(s):  
Density Functional Theory ◽  
Crystal Structures ◽  
Density Functional ◽  
Unit Cell ◽  
Organic Crystal ◽  
Large Temperature ◽  
Unit Cell Parameters ◽  
Functional Theory ◽  
Cell Parameters ◽  
Experimental Crystal

This paper describes the validation of a dispersion-corrected density functional theory (d-DFT) method for the purpose of assessing the correctness of experimental organic crystal structures and enhancing the information content of purely experimental data. 241 experimental organic crystal structures from the August 2008 issue of Acta Cryst. Section E were energy-minimized in full, including unit-cell parameters. The differences between the experimental and the minimized crystal structures were subjected to statistical analysis. The r.m.s. Cartesian displacement excluding H atoms upon energy minimization with flexible unit-cell parameters is selected as a pertinent indicator of the correctness of a crystal structure. All 241 experimental crystal structures are reproduced very well: the average r.m.s. Cartesian displacement for the 241 crystal structures, including 16 disordered structures, is only 0.095 Å (0.084 Å for the 225 ordered structures). R.m.s. Cartesian displacements above 0.25 Å either indicate incorrect experimental crystal structures or reveal interesting structural features such as exceptionally large temperature effects, incorrectly modelled disorder or symmetry breaking H atoms. After validation, the method is applied to nine examples that are known to be ambiguous or subtly incorrect.

Predicted and experimental crystal structures of ethyl-tert-butyl ether

2011 ◽  
Vol 67 (2) ◽  
pp. 155-162 ◽  
Author(s):  
Sonja M. Hammer ◽  
Edith Alig ◽  
Lothar Fink ◽  
Martin U. Schmidt
Keyword(s):  
Crystal Structure ◽  
Crystal Structures ◽  
Global Minimum ◽  
Lattice Energy ◽  
Real Space ◽  
Energy Structure ◽  
Butyl Ether ◽  
Crystallization Experiments ◽  
Rank 2 ◽  
Experimental Crystal

Possible crystal structures of ethyl-tert-butyl ether (ETBE) were predicted by global lattice-energy minimizations using the force-field approach. 33 structures were found within an energy range of 2 kJ mol−1 above the global minimum. Low-temperature crystallization experiments were carried out at 80–160 K. The crystal structure was determined from X-ray powder data. ETBE crystallizes in C2/m, Z = 4, with molecules on mirror planes. The ETBE molecule adopts a trans conformation with a (CH3)3C—O—C—C torsion angle of 180°. The experimental structure corresponds with high accuracy to the predicted structure with energy rank 2, which has an energy of 0.54 kJ mol−1 above the global minimum and is the most dense low-energy structure. In some crystallization experiments a second polymorph was observed, but the quality of the powder data did not allow the determination of the crystal structure. Possibilities and limitations are discussed for solving crystal structures from powder diffraction data by real-space methods and lattice-energy minimizations.

Predicted crystal structures of tetramethylsilane and tetramethylgermane and an experimental low-temperature structure of tetramethylsilane

2010 ◽  
Vol 66 (2) ◽  
pp. 229-236 ◽  
Author(s):  
Alexandra K. Wolf ◽  
Jürgen Glinnemann ◽  
Lothar Fink ◽  
Edith Alig ◽  
Michael Bolte ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Low Temperature ◽  
Crystal Structures ◽  
Ambient Pressure ◽  
Lattice Energy ◽  
Energy Structure ◽  
Temperature Phase ◽  
Temperature Structure ◽  
Field Methods ◽  
Experimental Crystal

No crystal structure at ambient pressure is known for tetramethylsilane, Si(CH3)4, which is used as a standard in NMR spectroscopy. Possible crystal structures were predicted by global lattice-energy minimizations using force-field methods. The lowest-energy structure corresponds to the high-pressure room-temperature phase (Pa\overline{3}, Z = 8). Low-temperature crystallization at 100 K resulted in a single crystal, and its crystal structure has been determined. The structure corresponds to the predicted structure with the second lowest energy rank. In X-ray powder analyses this is the only observed phase between 80 and 159 K. For tetramethylgermane, Ge(CH_3)_4, no experimental crystal structure is known. Global lattice-energy minimizations resulted in 47 possible crystal structures within an energy range of 5 kJ mol−1. The lowest-energy structure was found in Pa\overline{3}, Z = 8.

scholarly journals Accurate Lattice Energies for Molecular Crystals from Experimental Crystal Structures

2018 ◽  
Vol 14 (3) ◽  
pp. 1614-1623 ◽  
Author(s):  
Sajesh P. Thomas ◽  
Peter R. Spackman ◽  
Dylan Jayatilaka ◽  
Mark A. Spackman
Keyword(s):  
Crystal Structures ◽  
Molecular Crystals ◽  
Lattice Energies ◽  
Experimental Crystal

Structural insight from intermolecular interactions and energy framework analyses of 2-substituted 6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazolin-11-ones

2021 ◽  
Vol 77 (3) ◽  
Author(s):  
Akmaljon G. Tojiboev ◽  
Burkhon Zh. Elmuradov ◽  
Halima Mouhib ◽  
Kambarali K. Turgunov ◽  
Askar Sh. Abdurazakov ◽  
...  
Keyword(s):  
Hydrogen Bonds ◽  
Crystal Structures ◽  
Gas Phase ◽  
Intermolecular Interactions ◽  
Correction Term ◽  
Three Dimensional ◽  
Dispersion Interactions ◽  
Additional Information ◽  
Experimental Crystal ◽  
The Impact

The crystal structures of three mackinazolinone derivatives (2-amino-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazolin-11-one at room temperature, and 2-nitro-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazolin-11-one and N-(11-oxo-6,8,9,11-tetrahydro-7H-pyrido[2,1-b]quinazolin-2-yl)benzamide at 100 K) are explored using X-ray crystallography. To delineate the different intermolecular interactions and the respective interaction energies in the crystal architectures, energy framework analyses were carried out using the CE-B3LYP/6-31G(d,p) method implemented in the CrystalExplorer software. In the structures the different molecules are linked by C—H...O, C—H...N and N—H...O hydrogen bonds. Together with these hydrogen bonds, C—H...π and C—O...π interactions are involved in the formation of a three-dimensional crystal network. A Hirshfeld surface analysis allows the visualization of the two-dimensional fingerprint plots and the quantification of the contributions of H...H, H...C/C...H and H...O/O...H contacts throughout the different crystal structures. To obtain additional information on the intrinsic properties of our targets and to compare the experimental crystal structures with their respective conformations in the gas phase, quantum chemical calculations at the B3LYP-D3BJ/6-311++G(d,p) level of theory, including Grimme's D3 correction term and BJ damping functions, were carried out to account for intramolecular dispersion interactions. The identified energy gaps between the highest occupied and the lowest unoccupied molecular orbitals (HOMO–LUMO gap) of our targets in the gas phase and in two implicit solvents (methanol and dimethyl sulfoxide) allow us to quantify the impact of different substituents on the reactivity of mackinazolinone derivatives.

scholarly journals Theoretical Prediction of Crystal Polymorphs for Organic Molecules

2014 ◽  
Vol 70 (a1) ◽  
pp. C1626-C1626
Author(s):  
Shigeaki Obata ◽  
Mitsuaki Sato ◽  
Hitoshi Goto
Keyword(s):  
Crystal Structure ◽  
Crystal Structures ◽  
Structure Prediction ◽  
High Speed ◽  
Prediction Method ◽  
Energy Calculation ◽  
Crystal Polymorphism ◽  
Energy Evaluation ◽  
Target Molecules ◽  
Experimental Crystal

Crystal structure prediction is one of the useful theoretical tools for designing and synthesizing new materials in pharmaceutical therapeutics and industrial electronics. Furthermore, the prediction can provide immense valuable scientific knowledge on a crystal growth, polymorphism and many properties of organic molecular crystals. Therefore, we have started the development of high-speed and high-accurate prediction method for organic molecular crystal structures [1,2]. In this work, we demonstrate the theoretical predictions of crystal structures of fourteen target molecules that were used in the international competitions known as CSP blind tests hosted by CCDC [3]. All strategies required for crystal lattice construction expanded to a given effective crystal radius, crystal energy calculation with the reliable molecular force field (MMFF94s) and exhaustive geometry search included a variety of crystal polymorphism are implemented into CONFLEX program [1]. As the results of the applications, we confirmed in all cases of target molecules that, at least, one calculated crystal structure in agreement with the corresponding observed ones can be found. Essential ability required for the prediction method to survive the CSP competitions is that the experimental crystal structure can computationally reproduce within top 3 of most stable structures in crystal energy evaluation. In these tests, only three applications to the target I (Orth. polymorph), II and VIII can successfully satisfy the demand. Details will be discussed in this conference.

Synthon polymorphs of 1 : 1 co-crystal of 5-fluorouracil and 4-hydroxybenzoic acid: their relative stability and solvent polarity dependence of grinding outcomes

CrystEngComm ◽  
2014 ◽  
Vol 16 (28) ◽  
pp. 6450-6458 ◽  
Author(s):  
Song Li ◽  
Jia-Mei Chen ◽  
Tong-Bu Lu
Keyword(s):  
Crystal Structures ◽  
Relative Stability ◽  
Solvent Polarity ◽  
Hydroxybenzoic Acid

Two synthon polymorphs of 1 : 1 co-crystals of 5-fluorouracil and 4-hydroxybenzoic acid were synthesized, and the crystal structures were determined.

scholarly journals Data mining of iron(II) and iron(III) bond-valence parameters, and their relevance for macromolecular crystallography

2017 ◽  
Vol 73 (4) ◽  
pp. 316-325 ◽  
Author(s):  
Heping Zheng ◽  
Karol M. Langner ◽  
Gregory P. Shields ◽  
Jing Hou ◽  
Marcin Kowiel ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Metal Binding ◽  
Binding Sites ◽  
Structural Data ◽  
Bond Valence ◽  
Oxidation States ◽  
Experimental Crystal ◽  
Nitrogen Bonds ◽  
Almost All ◽  
Bond Valence Model

The bond-valence model is a reliable way to validate assumed oxidation states based on structural data. It has successfully been employed for analyzing metal-binding sites in macromolecule structures. However, inconsistent results for heme-based structures suggest that some widely used bond-valenceR0parameters may need to be adjusted in certain cases. Given the large number of experimental crystal structures gathered since these initial parameters were determined and the similarity of binding sites in organic compounds and macromolecules, the Cambridge Structural Database (CSD) is a valuable resource for refining metal–organic bond-valence parameters.R0bond-valence parameters for iron(II), iron(III) and other metals have been optimized based on an automated processing of all CSD crystal structures. Almost allR0bond-valence parameters were reproduced, except for iron–nitrogen bonds, for which distinctR0parameters were defined for two observed subpopulations, corresponding to low-spin and high-spin states, of iron in both oxidation states. The significance of this data-driven method for parameter discovery, and how the spin state affects the interpretation of heme-containing proteins and iron-binding sites in macromolecular structures, are discussed.

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