In silico repurposing of antipsychotic drugs for Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most prevalent form of dementia and represents one of the highest unmet requirements in medicine today. There is shortage of novel molecules entering into market because of poor pharmacokinetic properties and safety issues. Drug repurposing offers an opportunity to reinvigorate the slowing drug discovery process by finding new uses for existing drugs. The major advantage of the drug repurposing approach is that the safety issues are already investigated in the clinical trials and the drugs are commercially available in the marketplace. As this approach provides an effective solution to hasten the process of providing new alternative drugs for AD, the current study shows the molecular interaction of already known antipsychotic drugs with the different protein targets implicated in AD using in silico studies. RESULT: A computational method based on ligand-protein interaction was adopted in present study to explore potential antipsychotic drugs for the treatment of AD. The screening of approximately 150 antipsychotic drugs was performed on five major protein targets (AChE, BuChE, BACE 1, MAO and NMDA) by molecular docking. In this study, for each protein target, the best drug was identified on the basis of dock score and glide energy. The top hits were then compared with the already known inhibitor of the respective proteins. Some of the drugs showed relatively better docking score and binding energies as compared to the already known inhibitors of the respective targets. Molecular descriptors like molecular weight, number of hydrogen bond donors, acceptors, predicted octanol/water partition coefficient and percentage human oral absorption were also analysed to determine the in silico ADME properties of these drugs and all were found in the acceptable range and follows Lipinski's rule. CONCLUSION: The present study have led to unravel the potential of leading antipsychotic drugs such as pimozide, bromperidol, melperone, anisoperidone, benperidol and anisopirol against multiple targets associated with AD. Benperidol was found to be the best candidate drug interacting with different target proteins involved in AD.

Efficacy of geraniol but not of β-ionone or their combination for the chemoprevention of rat colon carcinogenesis

β-ionone (βI), a cyclic isoprenoid, and geraniol (GO), an acyclic monoterpene, represent a promising class of dietary chemopreventive agents against cancer, whose combination could result in synergistic anticarcinogenic effects. The chemopreventive activities of βI and GO were evaluated individually or in combination during colon carcinogenesis induced by dimethylhydrazine in 48 3-week-old male Wistar rats (12 per group) weighing 40-50 g. Animals were treated for 9 consecutive weeks with βI (16 mg/100 g body weight), GO (25 mg/100 g body weight), βI combined with GO or corn oil (control). Number of total aberrant crypt foci (ACF) and of ACF ≥4 crypts in the distal colon was significantly lower in the GO group (66 ± 13 and 9 ± 2, respectively) compared to control (102 ± 9 and 17 ± 3) and without differences in the βI (91 ± 11 and 14 ± 3) and βI+GO groups (96 ± 5 and 19 ± 2). Apoptosis level, identified by classical apoptosis morphological criteria, in the distal colon was significantly higher in the GO group (1.64 ± 0.06 apoptotic cells/mm²) compared to control (0.91 ± 0.07 apoptotic cells/mm²). The GO group presented a 0.7-fold reduction in Bcl-2 protein expression (Western blot) compared to control. Colonic mucosa concentrations of βI and GO (gas chromatography/mass spectrometry) were higher in the βI and GO groups, respectively, compared to the control and βI+GO groups. Therefore, GO, but not βI, represents a potential chemopreventive agent in colon carcrvpdate=20110329inogenesis. Surprisingly, the combination of isoprenoids does not represent an efficient chemopreventive strategy.

Efficacy of geraniol but not of ß-ionone or their combination for the chemoprevention of rat colon carcinogenesis.

ß-ionone (ßI), a cyclic isoprenoid, and geraniol (GO), an acyclic monoterpene, represent a promising class of dietary chemopreventive agents against cancer, whose combination could result in synergistic anticarcinogenic effects. The chemopreventive activities of ßI and GO were evaluated individually or in combination during colon carcinogenesis induced by dimethylhydrazine in 48 3-week-old male Wistar rats (12 per group) weighing 40-50 g. Animals were treated for 9 consecutive weeks with ßI (16 mg/100 g body weight), GO (25 mg/100 g body weight), ßI combined with GO or corn oil (control). Number of total aberrant crypt foci (ACF) and of ACF ≥4 crypts in the distal colon was significantly lower in the GO group (66 ± 13 and 9 ± 2, respectively) compared to control (102 ± 9 and 17 ± 3) and without differences in the ßI (91 ± 11 and 14 ± 3) and ßI+GO groups (96 ± 5 and 19 ± 2). Apoptosis level, identified by classical apoptosis morphological criteria, in the distal colon was significantly higher in the GO group (1.64 ± 0.06 apoptotic cells/mm²) compared to control (0.91 ± 0.07 apoptotic cells/mm²). The GO group presented a 0.7-fold reduction in Bcl-2 protein expression (Western blot) compared to control. Colonic mucosa concentrations of ßI and GO (gas chromatography/mass spectrometry) were higher in the ßI and GO groups, respectively, compared to the control and ßI+GO groups. Therefore, GO, but not ßI, represents a potential chemopreventive agent in colon carcinogenesis. Surprisingly, the combination of isoprenoids does not represent an efficient chemopreventive strategy.

Fragrance material review on methyl-alpha-ionone.

A toxicologic and dermatologic review of methyl-alpha-ionone when used as a fragrance ingredient is presented.

Fragrance material review on alpha-iso-methylionone.

A toxicologic and dermatologic review of alpha-iso-methylionone when used as a fragrance ingredient is presented.

Fragrance material review on alpha-ionone.

A toxicologic and dermatologic review of alpha-ionone when used as a fragrance ingredient is presented.

Fragrance material review on cis-beta-damascone.

A toxicologic and dermatologic review of cis-beta-damascone when used as a fragrance ingredient is presented.

A toxicologic and dermatologic assessment of ionones when used as fragrance ingredients.

An evaluation and review of a structurally related group of fragrance materials.

Fragrance material review on trans,trans-delta-damascone.

A toxicologic and dermatologic review of trans,trans-delta-damascone when used as a fragrance ingredient is presented.

Fragrance material review on isodamascone (isomer unspecified).

A toxicologic and dermatologic review of isodamascone when used as a fragrance ingredient is presented.

Fragrance material review on 6-methyl-beta-ionone.

A toxicologic and dermatologic review of 6-methyl-beta-ionone when used as a fragrance ingredient is presented.

Fragrance material review on beta-ionone.

A toxicologic and dermatologic review of beta-ionone when used as a fragrance ingredient is presented.

Fragrance material review on iso-methyl-beta-ionone.

A toxicologic and dermatologic review of iso-methyl-beta-ionone when used as a fragrance ingredient is presented.

Fragrance material review on trans-beta-damascone.

A toxicologic and dermatologic review of trans-beta-damascone when used as a fragrance ingredient is presented.

Fragrance material review on ionone.

A toxicologic and dermatologic review of ionone when used as a fragrance ingredient is presented.

Fragrance material review on dihydro-beta-ionone.

A toxicologic and dermatologic review of dihydro-beta-ionone when used as a fragrance ingredient is presented.

Fragrance material review on alpha-damascone.

A toxicologic and dermatologic review of alpha-damascone when used as a fragrance ingredient is presented.

Fragrance material review on trans-beta-ionone.

A toxicologic and dermatologic review of trans-beta-Ionone when used as a fragrance ingredient is presented.

Fragrance material review on delta-damascone.

A toxicologic and dermatologic review of delta-damascone when used as a fragrance ingredient is presented.

Fragrance material review on methyl ionone (mixture of isomers).

A toxicologic and dermatologic review of methyl ionone when used as a fragrance ingredient is presented.