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Investigation of the structure requirement for 5-HT? binding affinity of arylsulfonyl derivatives: a computational study.

ABSTRACT: 5-HT(6) receptor has been implicated in a series of diseases including anxiety, depression, schizophrenia and cognitive dysfunctions. 5-HT(6) ligands have been reported to play a significant role in the treatment for central nervous system (CNS) diseases. Presently, a large series of 223 5-HT(6) ligands were studied using a combinational method by 3D-QSAR, molecular docking and molecular dynamics calculations for further improvement of potency. The optimal 3D models exhibit satisfying statistical results with r(2) (ncv), q(2) values of 0.85 and 0.50 for CoMFA, 0.81 and 0.53 for CoMSIA, respectively. Their predictive powers were validated by external test set, showing r(2) (pred) of 0.71 and 0.76. The contour maps also provide a visual representation of contributions of steric, electrostatic, hydrophobic and hydrogen bond fields as well as the prospective binding models. In addition, the agreement between 3D-QSAR, molecular docking and molecular dynamics simulation proves the rationality of the developed models. These results, we hope, may be helpful in designing novel and potential 5-HT(6) ligands.

SUBMITTER: Hao M

PROVIDER: S-EPMC3179148 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Investigation of the structure requirement for 5-HT₆ binding affinity of arylsulfonyl derivatives: a computational study.

Hao Ming M Li Yan Y Li Hanqing H Zhang Shuwei S

International journal of molecular sciences 20110808 8

5-HT(6) receptor has been implicated in a series of diseases including anxiety, depression, schizophrenia and cognitive dysfunctions. 5-HT(6) ligands have been reported to play a significant role in the treatment for central nervous system (CNS) diseases. Presently, a large series of 223 5-HT(6) ligands were studied using a combinational method by 3D-QSAR, molecular docking and molecular dynamics calculations for further improvement of potency. The optimal 3D models exhibit satisfying statistica ...[more]

PMID: 21954341

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Project description:Ab initio calculations were carried out to understand the reactivity and stability of some uracil derivatives, cytosine, 1-methyl cytosine, and cytidine in solvents, water, dimethyl sulfoxide (DMSO), n-octanol, and chloroform. Geometries were fully optimized at MP2 and B3LYP using the 6-31+G(d,p) basis set by applying the Solvation Model on Density (SMD) in solvent systems. The syn conformer of cytidine (cytidine II) is the most stable conformer in the gas phase, while the anticonformer (cytidine IV) is most stable in all of the solvents. Solvation free energy and polarizability values in different solvents decrease in the order water > DMSO > n-octanol > chloroform, while dipole moment, first-order hyperpolarizability, and HOMO-LUMO energy gap values follow the order of polar protic solvent (water and n-octanol) > polar aprotic solvent (DMSO) > nonpolar solvent (chloroform). The solvation free energy, dipole moment, polarizability, and first-order hyperpolarizability values also follow the order of cytosine > 1-methyl cytosine > cytidine. To illustrate that the molecular properties correlate well with the reactivity of the molecules, ab initio calculations were carried out for the reaction of uracil derivatives with Br2 in the gas phase, water, DMSO, n-octanol, and chloroform. All ground and transition state geometries were fully optimized at B3LYP/6-31+G(d,p), and energies were also calculated at G3MP2 for cytosine and 1-methyl cytosine. For cytosine and 1-methyl cytosine, Gibbs energies of activation decrease with the polarity of the solvent that is chloroform > n-octanol > DMSO > water, while the Gibbs energies of activation for the reaction with cytidine decrease in the order of water > DMSO > n-octanol > chloroform. These results suggest that solvent polarity is very important for the stability and reactivity of uracil derivatives. Hydrogen bonding may also play an important role mainly for cytidine. Free energies of activation decrease with the size of the molecule, i.e., cytosine > 1-methyl cytosine > cytidine.

Dataset Information

Investigation of the structure requirement for 5-HT? binding affinity of arylsulfonyl derivatives: a computational study.

Publications

Investigation of the structure requirement for 5-HT₆ binding affinity of arylsulfonyl derivatives: a computational study.

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