{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T05:03:20Z","timestamp":1792645400728,"version":"4.5.0"},"reference-count":56,"publisher":"American Chemical Society (ACS)","issue":"12","license":[{"start":{"date-parts":[[2021,3,16]],"date-time":"2021-03-16T00:00:00Z","timestamp":1615852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,3,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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\u2019s disease. As a springboard to explore new anti-cancer and anti-Alzheimer\u2019s 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\u2032,4\u2032,6-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 \u03b2-addition adduct. The top-ranked compounds also conferred favorable in silico pharmacokinetic properties.<\/jats:p>","DOI":"10.1021\/acsomega.1c00137","type":"journal-article","created":{"date-parts":[[2021,3,16]],"date-time":"2021-03-16T03:04:32Z","timestamp":1615863872000},"page":"8403-8417","source":"Crossref","is-referenced-by-count":41,"title":["Potential Cancer- and Alzheimer\u2019s Disease-Targeting\nPhosphodiesterase Inhibitors from\n                    <i>Uvaria alba<\/i>\n                    : Insights from\n                    <i>In Vitro<\/i>\n                    and Consensus Virtual Screening"],"prefix":"10.1021","volume":"6","author":[{"given":"Mark Tristan","family":"Quimque","sequence":"first","affiliation":[{"name":"University of Santo Tomas , , Espan\u0303a Blvd. , ,","place":["Manila, Philippines, 1015"]},{"name":"University of Santo Tomas , , Espan\u0303a Blvd. , ,","place":["Manila, Philippines, 1015"]},{"name":"Mindanao State University-Iligan Institute of Technology , , Tibanga, ,","place":["Iligan\nCity, Philippines, 9200"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6055-0886","authenticated-orcid":true,"given":"Kin Israel","family":"Notarte","sequence":"additional","affiliation":[{"name":"University of Santo Tomas , , Espan\u0303a Blvd. , ,","place":["Manila, Philippines, 1015"]},{"name":"University of Santo Tomas , , Espan\u0303a Blvd. , ,","place":["Manila, Philippines, 1015"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianne","family":"Letada","sequence":"additional","affiliation":[{"name":"University of Santo Tomas , , Espan\u0303a Blvd. , ,","place":["Manila, Philippines, 1015"]},{"name":"University of Santo Tomas , , Espan\u0303a Blvd. , ,","place":["Manila, Philippines, 1015"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6168-3947","authenticated-orcid":true,"given":"Rey Arturo","family":"Fernandez","sequence":"additional","affiliation":[{"name":"University of Santo Tomas , , Espan\u0303a Blvd. , ,","place":["Manila, Philippines, 1015"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9156-8587","authenticated-orcid":true,"suffix":"IV","given":"Delfin Yn\u0303igo","family":"Pilapil","sequence":"additional","affiliation":[{"name":"University of Santo Tomas , , Espan\u0303a Blvd. , ,","place":["Manila, Philippines, 1015"]},{"name":"University of Santo Tomas , , Espan\u0303a Blvd. , ,","place":["Manila, Philippines, 1015"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirstin Rhys","family":"Pueblos","sequence":"additional","affiliation":[{"name":"University of Santo Tomas , , Espan\u0303a Blvd. , ,","place":["Manila, Philippines, 1015"]},{"name":"University of Santo Tomas , , Espan\u0303a Blvd. , ,","place":["Manila, Philippines, 1015"]},{"name":"Mindanao State University-Iligan Institute of Technology , , Tibanga, ,","place":["Iligan\nCity, Philippines, 9200"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay Carl","family":"Agbay","sequence":"additional","affiliation":[{"name":"Mindanao State University-Iligan Institute of Technology , , Tibanga, ,","place":["Iligan\nCity, Philippines, 9200"]},{"name":"Philippine Science High School\ue5f8Central Mindanao Campus , , ,","place":["Balo-i, Lanao del Norte, Philippines, 9217"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans-Martin","family":"Dahse","sequence":"additional","affiliation":[{"name":"Hans-Kno\u0308ll-Institute (HKI) , , ,","place":["Jena, Germany, D-07745"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arlette","family":"Wenzel-Storjohann","sequence":"additional","affiliation":[{"name":"GEOMAR Helmholtz Centre for Ocean Research Kiel , , Am Kiel-Kanal, ,","place":["Kiel, Germany, 24106"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7841-6271","authenticated-orcid":true,"given":"Deniz","family":"Tasdemir","sequence":"additional","affiliation":[{"name":"GEOMAR Helmholtz Centre for Ocean Research Kiel , , Am Kiel-Kanal, ,","place":["Kiel, Germany, 24106"]},{"name":"Kiel University , , Christian-Albrechts-Platz 4 , ,","place":["Kiel, Germany, 24118"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4288-7602","authenticated-orcid":true,"given":"Abbas","family":"Khan","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University , , 800 Dongchuan Road , Minhang District, ,","place":["Shanghai, China, 200240"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4200-7502","authenticated-orcid":true,"given":"Dong-Qing","family":"Wei","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University , , 800 Dongchuan Road , Minhang District, ,","place":["Shanghai, China, 200240"]},{"name":"Peng Cheng Laboratory , Vanke Cloud City Phase I Building 8, Xili Street , Nashan District, , ,","place":["Shenzhen, Guangdong, P.R. 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