Potential Cancer- and Alzheimer’s Disease-Targeting Phosphodiesterase Inhibitors from <i>Uvaria alba</i>: Insights from <i>In Vitro</i> and Consensus Virtual Screening

Inhibition of the major cyclic adenosine monophosphate-metabolizing enzyme PDE4 has shown potential for discovery drugs cancer, inflammation, and neurodegenerative disorders such as Alzheimer’s disease. As a springboard to explore new anti-cancer anti-Alzheimer’s chemical prototypes from rare Annonaceae species, present study evaluated anti-PDE4B along with antiproliferative anti-cholinesterase activities extracts Philippine endemic species Uvaria alba using in vitro assays framed resulting biological significance through computational binding reactivity-based experiments. Thus, B2B-inhibiting dichloromethane sub-extract (UaD) U. elicited activity against chronic myelogenous leukemia (K-562) cytostatic effects human cervical cancer (HeLa). The extract also profoundly inhibited acetylcholinesterase (AChE), an involved progression diseases. Chemical profiling analysis bioactive identified 18 putative secondary metabolites. Molecular docking molecular dynamics simulations showed strong free energy mechanisms dynamic stability at 50-ns catalytic domains B2B, ubiquitin-specific peptidase 14, Kelch-like ECH-associated protein 1 (KEAP-1 Kelch domain) benzylated dihydroflavone dichamanetin (16), AChE KEAP-1 BTB domain 3-(3,4-dihydroxybenzyl)-3′,4′,6-trihydroxy-2,4-dimethoxychalcone (8) grandifloracin (15), respectively. Density functional theory calculations demonstrate Michael addition reaction most electrophilic metabolite kinetically stable (15) Cys151 illustrated favorable formation β-addition adduct. top-ranked compounds conferred silico pharmacokinetic properties.