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Discovery of a novel acetylcholinesterase inhibitor by structure-based virtual screening techniques.
Bioorg Med Chem Lett. 2012 May 01; 22(9):3181-7.BM

Abstract

Acetylcholinesterase (AChE) is considered to be one of the most important targets for the treatment of Alzheimer's disease (AD). Previously our group has reported a series of tacrine-based hybrids as potent AChE inhibitors (AChEI). To discover more novel scaffolds, molecular docking and dynamics stimulation were applied to acquire the binding models of AChE with the most prominent compounds from our work. A structure-based pharmacophore model plus shape constraints was generated from the binding models and it was then employed to virtually screen commercial databases, giving a focused hit list of candidates. Subsequently, we scored the hit compounds by their molecular binding energies, which were calculated by MM/PBSA method. Fifteen compounds were selected and purchased for testing their anti-AChE effects, while seven of them showed inhibitory effects with IC(50) values ranging from 1.5 to 9.8 μM. The drug-like properties of these compounds, including LogD, AlogP, molecular volume and Lipinski rule of five, were also calculated. Compounds 12 and 16 (IC(50)=2.5 and 1.5 μM, respectively) exhibited potent activity and acceptable drug-like properties, thus might serve as leads for further modification. The data suggest that the presented model might be a valid approach for identification and development of new AChEIs.

Authors+Show Affiliations

State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22472693

Citation

Chen, Yao, et al. "Discovery of a Novel Acetylcholinesterase Inhibitor By Structure-based Virtual Screening Techniques." Bioorganic & Medicinal Chemistry Letters, vol. 22, no. 9, 2012, pp. 3181-7.
Chen Y, Fang L, Peng S, et al. Discovery of a novel acetylcholinesterase inhibitor by structure-based virtual screening techniques. Bioorg Med Chem Lett. 2012;22(9):3181-7.
Chen, Y., Fang, L., Peng, S., Liao, H., Lehmann, J., & Zhang, Y. (2012). Discovery of a novel acetylcholinesterase inhibitor by structure-based virtual screening techniques. Bioorganic & Medicinal Chemistry Letters, 22(9), 3181-7. https://doi.org/10.1016/j.bmcl.2012.03.046
Chen Y, et al. Discovery of a Novel Acetylcholinesterase Inhibitor By Structure-based Virtual Screening Techniques. Bioorg Med Chem Lett. 2012 May 1;22(9):3181-7. PubMed PMID: 22472693.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discovery of a novel acetylcholinesterase inhibitor by structure-based virtual screening techniques. AU - Chen,Yao, AU - Fang,Lei, AU - Peng,Sixun, AU - Liao,Hong, AU - Lehmann,Jochen, AU - Zhang,Yihua, Y1 - 2012/03/16/ PY - 2012/02/14/received PY - 2012/03/09/revised PY - 2012/03/10/accepted PY - 2012/4/5/entrez PY - 2012/4/5/pubmed PY - 2012/10/12/medline SP - 3181 EP - 7 JF - Bioorganic & medicinal chemistry letters JO - Bioorg Med Chem Lett VL - 22 IS - 9 N2 - Acetylcholinesterase (AChE) is considered to be one of the most important targets for the treatment of Alzheimer's disease (AD). Previously our group has reported a series of tacrine-based hybrids as potent AChE inhibitors (AChEI). To discover more novel scaffolds, molecular docking and dynamics stimulation were applied to acquire the binding models of AChE with the most prominent compounds from our work. A structure-based pharmacophore model plus shape constraints was generated from the binding models and it was then employed to virtually screen commercial databases, giving a focused hit list of candidates. Subsequently, we scored the hit compounds by their molecular binding energies, which were calculated by MM/PBSA method. Fifteen compounds were selected and purchased for testing their anti-AChE effects, while seven of them showed inhibitory effects with IC(50) values ranging from 1.5 to 9.8 μM. The drug-like properties of these compounds, including LogD, AlogP, molecular volume and Lipinski rule of five, were also calculated. Compounds 12 and 16 (IC(50)=2.5 and 1.5 μM, respectively) exhibited potent activity and acceptable drug-like properties, thus might serve as leads for further modification. The data suggest that the presented model might be a valid approach for identification and development of new AChEIs. SN - 1464-3405 UR - https://www.unboundmedicine.com/medline/citation/22472693/Discovery_of_a_novel_acetylcholinesterase_inhibitor_by_structure_based_virtual_screening_techniques_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0960-894X(12)00367-8 DB - PRIME DP - Unbound Medicine ER -