Integrative computational, synthetic, experimental evaluation of targeted inhibitors against matrix metalloproteinase-9: Toward precision modulation of proteolytic activity
Year: 2026
Type: article
Abstract: Matrix metalloproteinase-9 (MMP-9) is a zinc-dependent enzyme that degrades the extracellular matrix and is involved in various diseases, including rheumatoid arthritis, atherosclerosis, tumor invasion, and metastasis. Despite the development of inhibitors, none have succeeded in trials. Our goal was to find potential inhibitors to regulate its proteolytic activity. Ligand- and structure-based drug design approaches were explored to identify inhibitors against wild-type (1GKC) and mutant (2OW1) MMP-9. A pharmacophore model was created, and drug-like molecules were prioritized to guide the development of benzamide and 1H-indole-2-carboxamide derivatives. These compounds were synthesized and characterized using ¹H NMR, 13C NMR, and HRMS (ESI). An experimental evaluation assessed their inhibitory potential and IC50 values against MMP-9. Most tested inhibitors fit the pharmacophore model, which consists of three aromatic/hydrophobic spheres and two hydrogen-bond donors/acceptors. Compounds 1, 2, 8, 10, 20, 21, 27, and 29 exhibited significant inhibition (P < 0.0001) of over 60%. Compounds 2 and 20 inhibited growth by over 70%, with IC50 values of 28.59 μM and 30.82 μM, respectively. The IF docking showed strong binding for these, with scores of -9.179 and -10.739 kcal/mol. The alignment between the computational approach and experimental validation reinforces the inhibitor's specificity and potency, confirms the docking model, and suggests that the predicted binding pose represents key biological interactions.
Source: PLoS ONE
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,382
Funders: Deanship of Scientific Research, King Khalid University, Donostia International Physics Center, Taiwan Power Company, Foundation for the National Institutes of Health, American Cancer Society, Alzheimer's Association, Kavli Foundation, Grass Foundation, National Geographic Society, UNICEF, Takeda Science Foundation, Australian Nuclear Science and Technology Organisation, Prince Sattam bin Abdulaziz University, Henan Normal University, UK Research and Innovation, Environmental Restoration and Conservation Agency, Canada Research Coordinating Committee, Natural Science Foundation of Nantong City, Health Commission of Hunan Province, Ministry of Science and Technology, Pakistan, Korea Dementia Research Center, College of Family Physicians of Canada, National Institute for Health and Care Research, Royal Society, Newcastle University, University of Bath, Department of Science and Technology, Ministry of Science and Technology, India, Higher Education Authority, Deutsche Forschungsgemeinschaft, Ministry of Education, Culture, Sports, Science and Technology, National Natural Science Foundation of China, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Imam Mohammed Ibn Saud Islamic University, China Postdoctoral Science Foundation, Dalian University of Technology, Science and Technology Commission of Shanghai Municipality, National Research Foundation of Korea, Natural Science Foundation of Hebei Province, Hunan University, Narodowe Centrum Nauki, Vetenskapsrådet, University of Jordan, Far Eastern Memorial Hospital, Université Claude Bernard Lyon 1, Indian Institute of Science Education and Research Pune, Environment and Climate Change Canada, University of Hail, Universidade Estadual Paulista, Medizinische Universität Graz, State Key Laboratory of Chemo/Biosensing and Chemometrics, Taipei Veterans General Hospital, Hunan University of Chinese Medicine, Al-Zaytoonah University of Jordan, Fonds de recherche du Québec, National Institutes of Health, Centers for Disease Control and Prevention, Natural Sciences and Engineering Research Council of Canada, Engineering and Physical Sciences Research Council, Natural Environment Research Council, Australian Research Council, Japan Society for the Promotion of Science, Health Services and Delivery Research Programme, Fundamental Research Funds for the Central Universities, Deanship of Scientific Research, University of Jordan, National Institute on Aging, National Heart, Lung, and Blood Institute, Core Research for Evolutional Science and Technology, Natural Science Foundation of Zhejiang Province, Ministry of Health Office for Healthcare Transformation
OpenAlex ID: W7129283418