Potential Cancer- and Alzheimer’s Disease-Targeting Phosphodiesterase Inhibitors from Uvaria alba: Insights from In Vitro and Consensus Virtual Screening
| Autor: | Kin Israel Notarte, Arlette Wenzel-Storjohann, Dong-Qing Wei, Delfin Yñigo H. Pilapil, Deniz Tasdemir, Mark Tristan J. Quimque, Hans-Martin Dahse, Jay Carl M. Agbay, Kirstin Rhys S. Pueblos, arianne letada, Abbas Khan, Rey Arturo T. Fernandez, Allan Patrick G. Macabeo |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
chemistry.chemical_classification
0303 health sciences Virtual screening biology 010405 organic chemistry General Chemical Engineering Metabolite In silico In vitro toxicology General Chemistry biology.organism_classification 01 natural sciences Acetylcholinesterase In vitro 0104 chemical sciences 3. Good health HeLa Chemistry 03 medical and health sciences chemistry.chemical_compound Enzyme Biochemistry chemistry QD1-999 030304 developmental biology |
| Zdroj: | ACS Omega, Vol 6, Iss 12, Pp 8403-8417 (2021) |
| ISSN: | 2470-1343 |
| DOI: | 10.1021/acsomega.1c00137 |
| Popis: | Inhibition of the major cyclic adenosine monophosphate- metabolizing enzyme PDE4 has shown potential for the discovery of drugs for cancer, inflammation, and neurodegenerative disorders such as Alzheimer's disease. As a springboard to explore new anti-cancer and anti-Alzheimer's chemical prototypes from rare Annonaceae species, the present study evaluated anti-PDE4B along with antiproliferative and anti-cholinesterase activities of the extracts of the Philippine endemic species Uvaria alba using in vitro assays and framed the resulting biological significance through computational binding and reactivity-based experiments. Thus, the PDE4 B2B-inhibiting dichloromethane sub-extract (UaD) of U. alba elicited antiproliferative activity against chronic myelogenous leukemia (K-562) and cytostatic effects against human cervical cancer (HeLa). The extract also profoundly inhibited acetylcholinesterase (AChE), an enzyme involved in the progression of neurodegenerative diseases. Chemical profiling analysis of the bioactive extract identified 18 putative secondary metabolites. Molecular docking and molecular dynamics simulations showed strong free energy binding mechanisms and dynamic stability at 50- ns simulations in the catalytic domains of PDE4 B2B, ubiquitin-specific peptidase 14, and Kelch-like ECH-associated protein 1 (KEAP-1 Kelch domain) for the benzylated dihydroflavone dichamanetin (16), and of an AChE and KEAP-1 BTB domain for 3- (3,4-dihydroxybenzyl)-3',4',6-trihydroxy-2,4-dimethoxychalcone (8) and grandifloracin (15), respectively. Density functional theory calculations to demonstrate Michael addition reaction of the most electrophilic metabolite and kinetically stable grandifloracin (15) with Cys151 of the KEAP-1 BTB domain illustrated favorable formation of a β-addition adduct. The top-ranked compounds also conferred favorable in silico pharmacokinetic properties. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|