Computational and Experimental Assessments of Magnolol as a Neuroprotective Agent and Utilization of UiO-66(Zr) as Its Drug Delivery System

Joshua Santos; Mark Tristan Quimque; Rhenz Alfred Liman; Jay Carl Agbay; Allan Patrick G Macabeo; Mary Jho-Anne Corpuz; Yun-Ming Wang; Tsai-Te Lu; Chia-Her Lin; Oliver B Villaflores

doi:10.1021/acsomega.1c02555

Computational and Experimental Assessments of Magnolol as a Neuroprotective Agent and Utilization of UiO-66(Zr) as Its Drug Delivery System

ACS Omega. 2021 Sep 15;6(38):24382-24396. doi: 10.1021/acsomega.1c02555. eCollection 2021 Sep 28.

Authors

Joshua Santos^{1

2}, Mark Tristan Quimque^{1

3

4}, Rhenz Alfred Liman^{1

2}, Jay Carl Agbay^{4

5}, Allan Patrick G Macabeo³, Mary Jho-Anne Corpuz^{1

6

7}, Yun-Ming Wang⁸, Tsai-Te Lu⁹, Chia-Her Lin¹⁰, Oliver B Villaflores^{1

2

11}

Affiliations

¹ The Graduate School, University of Santo Tomas, España Blvd., 1015 Manila, Philippines.
² Phytochemistry Laboratory, Research Center for the Natural and Applied Sciences, University of Santo Tomas, España Blvd., 1015 Manila, Philippines.
³ Laboratory of Organic Reactivity, Discovery, and Synthesis (LORDS), Research Center for Natural and Applied Sciences, University of Santo Tomas, España Blvd., 1015 Manila, Philippines.
⁴ Department of Chemistry, College of Science and Mathematics, Mindanao State University-Iligan Institute of Technology, Tibanga, 9200 Iligan City, Philippines.
⁵ Philippine Science High School-Central Mindanao Campus, 9217 Balo-i, Lanao del Norte, Philippines.
⁶ Pharmacology Laboratory, Research Center for the Natural and Applied Sciences, University of Santo Tomas, España Blvd., 1015 Manila, Philippines.
⁷ Department of Pharmacy, Faculty of Pharmacy, University of Santo Tomas, España Blvd., 1015 Manila, Philippines.
⁸ Department of Biological Science and Technology, Institute of Molecular Medicine and Bioengineering, Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Chiao Tung University, 30010 Hsinchu, Taiwan.
⁹ Institute of Biomedical Engineering, National Tsing Hua University, 30013 Hsinchu, Taiwan.
¹⁰ College of Science, Chung Yuan Christian University, Zhongli District, 320 Taoyuan City, Taiwan.
¹¹ Department of Biochemistry, Faculty of Pharmacy, University of Santo Tomas, España Blvd., 1015 Manila, Philippines.

Abstract

The phenolic natural product magnolol exhibits neuroprotective properties through β-amyloid toxicity in PC-12 cells and ameliorative effects against cognitive deficits in a TgCRND8 transgenic mice model. Its bioavailability and blood-brain barrier crossing ability have been significantly improved using the metal-organic framework (MOF) UiO-66(Zr) as a drug delivery system (DDS). To investigate the neuroprotective effects of the Zr-based DDS, magnolol and magnolol-loaded-UiO-66(Zr) (Mag@UiO-66(Zr)) were evaluated for inhibitory activity against β-secretase and AlCl₃-induced neurotoxicity. Due to the moderate inhibition observed for magnolol in vitro, in silico binding studies were explored against β-secretase along with 11 enzymes known to affect Alzheimer's disease (AD). Favorable binding energies against CDK2, CKD5, MARK, and phosphodiesterase 3B (PDE3B) and dynamically stable complexes were noted through molecular docking and molecular dynamic simulation experiments, respectively. The magnolol-loaded DDS UiO-66(Zr) also showed enhanced neuroprotective activity against two pathological indices, namely, neutrophil infiltration and apoptotic neurons, in addition to damage reversal compared to magnolol. Thus, MOFs are promising drug delivery platforms for poorly bioavailable drugs.