The structure of haloperidol hydrobromide {4-[4-(4-chlorophenyl)-4-hydroxypiperidino]-4'-fluorobutyrophenone HBr}

Datta, N.; Mondal, Pradip Kumar; Pauling, Peter

doi:10.1107/s0567740879006828

Cited by 13 publications

(1 citation statement)

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“…The log P values were taken from Hansh et al and refs − . The starting geometries were taken either from the Cambridge Structural Database (pure molecule solid phase) − or from Protein Databank (in complex with a protein). − The crystal structures of dph, dzp, and ptn compounds were not available. Hence, these molecules were built manually, and the geometries optimized at the M062X/6-31G* level of theory with the SMD served as the starting structures for further conformational sampling.…”

Section: Methodsmentioning

confidence: 99%

Assessing the Accuracy and Performance of Implicit Solvent Models for Drug Molecules: Conformational Ensemble Approaches

et al. 2013

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The accuracy and performance of implicit solvent methods for solvation free energy calculations were assessed on a set of 20 neutral drug molecules. Molecular dynamics (MD) provided ensembles of conformations in water and water-saturated octanol. The solvation free energies were calculated by popular implicit solvent models based on quantum mechanical (QM) electronic densities (COSMO-RS, MST, SMD) as well as on molecular mechanical (MM) point-charge models (GB, PB). The performance of the implicit models was tested by a comparison with experimental water-octanol transfer free energies (ΔG(ow)) by using single- and multiconformation approaches. MD simulations revealed difficulties in a priori estimation of the flexibility features of the solutes from simple structural descriptors, such as the number of rotatable bonds. An increasing accuracy of the calculated ΔG(ow) was observed in the following order: GB1 ~ PB < GB7 ≪ MST < SMD ~ COSMO-RS with a clear distinction identified between MM- and QM-based models, although for the set excluding three largest molecules, the differences among COSMO-RS, MST, and SMD were negligible. It was shown that the single-conformation approach applied to crystal geometries provides a rather accurate estimate of ΔG(ow) for rigid molecules yet fails completely for the flexible ones. The multiconformation approaches improved the performance, but only when the deformation contribution was ignored. It was revealed that for large-scale calculations on small molecules a recent GB model, GB7, provided a reasonable accuracy/speed ratio. In conclusion, the study contributes to the understanding of solvation free energy calculations for physical and medicinal chemistry applications.

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Section: Methodsmentioning

confidence: 99%

Assessing the Accuracy and Performance of Implicit Solvent Models for Drug Molecules: Conformational Ensemble Approaches

et al. 2013

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The gradient‐optimized geometry of haloperidol at the 4‐21G level

1989

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The molecular structure of haloperidol as free base in its C(13)—C(14) trans form is optimized using Pulay's gradient method and a 4‐21G basis set without any geometrical constraints. The resulting structure is compared with the experimental structure of the free base in the C(13)—C(14) gauche form and with the experimental structure of the HBr salt of haloperidol in the C(13)—C(14) trans form. Apart from the obvious differences, the two rotameric forms of the free base show many similarities. This, together with the manner in which the differences of the two experimental structures are distributed over the haloperidol molecule, leads to the conclusion that the conspicuous differences between the experimental structures are caused by inaccuracies in the X‐ray determination of the HBr salt. Deviations of phenyl ring geometries from D6h symmetry and the asymmetry of the conformation around C(1)—C(9) could be rationalized by intramolecular effects.

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Molecular similarity and complementarity based on the theory of atoms in molecules

Popelier¹

1995

Molecular Similarity in Drug Design

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The structure of haloperidol hydrobromide {4-[4-(4-chlorophenyl)-4-hydroxypiperidino]-4'-fluorobutyrophenone HBr}

Cited by 13 publications

References 0 publications

Assessing the Accuracy and Performance of Implicit Solvent Models for Drug Molecules: Conformational Ensemble Approaches

Assessing the Accuracy and Performance of Implicit Solvent Models for Drug Molecules: Conformational Ensemble Approaches

The gradient‐optimized geometry of haloperidol at the 4‐21G level

Molecular similarity and complementarity based on the theory of atoms in molecules

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