THEORETICAL INVESTIGATION OF SELECTIVE INHIBITORY ACTIVITY OF CHROMONE-BASED COMPOUNDS AGAINST MONOAMINE OXIDASE (MAO)-A AND -B Intan Salsabila Putri 1,2 , Nur Farisya Shamsudin 2, Maryam Aisyah Abdullah 2, Mochamad Nurcholis 1 , Syahrul Imran 3, Chai Xin Yu 4, Chau Ling Tham 4, Mohd Fadhlizil Fasihi Mohd Aluwi 5 , Sze-Wei Leong 6 , Sentot Joko Raharjo 7, Zalikha Ibrahim 2 , Deri Islami 8 , Akm Moyeenul Huq 9, Muhammad Taher 10 , Kamal Rullah 2*
1 Department of Food Science and Technology, Faculty of Agricultural Technology, Brawijaya University, 65145 Malang,
Indonesia
2 Drug Discovery and Synthetic Chemistry Research Group, Department of Pharmaceutical Chemistry, Kulliyyah of Pharmacy, International Islamic University Malaysia, 25200 Kuantan, Pahang, Malaysia
3 Atta-ur-Rahman Institute for Natural Products Discovery (AuRIns), Universiti Teknologi MARA, Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia
4 Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang,
Selangor, Malaysia
5 Faculty of Industrial Sciences & Technology, Universiti Malaysia Pahang, Lebuhraya Tun Razak, 26300 Gambang, Pahang,
Malaysia
6 Department of Chemistry, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
7 Academic of Pharmacy and Food Analysis of Putra Indonesia Malang, Jl. Barito 5 Malang, 65141 East Java, Indonesia
8 Faculty of Pharmacy and Health Sciences, Universitas Abdurrab, Jalan Riau Ujung, 28292 Pekanbaru, Riau, Indonesia
9 Centre for Bio-Aromatic Research, Universiti Malaysia Pahang, Lebuhraya Tun Razak, 26300 Gambang, Pahang, Malaysia
10 Department of Pharmaceutical Technology, Kulliyyah of Pharmacy, International Islamic University Malaysia, 25200, Kuantan,
Pahang, Malaysia
Abstract
Monoamine oxidase (MAO) is essential for the breakdown of monoamine neurotransmitters, and targeting its activity with inhibitors is a promising strategy for treating neurodegenerative disorders, such as depression, Alzheimer, and Parkinson disease. In this study, we investigated the selective inhibitory activity of chromone-based compounds against MAO-A and MAO-B for neurodegenerative disease treatment. Thirty chromone derivatives have been reported in the literature as ligands for MAO-A and -B inhibitors. We used a molecular docking to determine the binding interaction of the most active compound with the targeted MAO-A and -B. The most active compound for MAO-A (2g) exhibited a higher -CDOCKER energy (35.0811 kcal/mol) than the co-crystallized ligand. However, Compound 2f, the most active compound for MAO-B, displayed a CDOCKER energy had similar binding patterns. Furthermore, we constructed a quantitative structure-activity relationship (QSAR) model to predict the properties and estimate IC50 values for 30 chromone derivatives functioning as MAO-A and MAO-B inhibitors. The model predictions were validated against experimental measurements. Our 2D QSAR model demonstrated robustness, with a statistically significant non-cross-validated coefficient (r2 < 0.9), crossvalidated correlation coefficient (q2 < 0.6), and predictive squared correlation coefficient (r2 pred < 0.8). Additionally, MD simulations confirmed the stable binding of compounds 2g and 2f with MAO-A and MAO-B, respectively, displaying substantial binding energy. The most effective pharmacophore model identified key features, such as hydrogen bond acceptors and hydrophobic interactions, that contribute significantly to inhibitory potency. This study offers valuable insight into the selection of compounds with improved selectivity for MAO inhibition.
