3D-QSAR assisted identification of FABP4 inhibitors: An effective scaffold hopping analysis/QSAR evaluation |
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| Institution: | 1. Department of Drug Sciences, University of Catania, V.le A. Doria 6, 95125 Catania, Italy;2. Department of Chemical Sciences, University of Catania, V.le A. Doria, 95125 Catania, Italy;3. Institute of Pharmaceutical Science, King’s College London, Stamford Street, London SE1 9NH, UK;4. King’s Forensics, School of Population Health & Environmental Sciences, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK;1. Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China;2. Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi, Chiba, 274-8510, Japan;1. NEUROFARBA, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy;2. Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK;3. NEUROFARBA, Sezione di Farmacologia e Tossicologia, Università degli Studi di Firenze, Viale Pieraccini 6, 50139 Firenze, Italy;1. College of Chemistry, Jilin University, No. 2699, Qianjin Street, Changchun, 130012, PR China;2. Tianjin Key Laboratory of Structure and Performance for Functional Molecules, Key Laboratory of Inorganic-Organic Hybrid Functional Material Chemistry, Ministry of Education, College of Chemistry, Tianjin Normal University, No. 393, Bin Shui West Road, Tianjin, 300387, PR China;1. Dipartimento NEUROFARBA, Sezione Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy;2. Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK;3. Dipartimento di Farmacia, Università degli Studi di Pisa, Via Bonanno 6, 56126 Pisa, Italy;4. NEUROFARBA, Sezione Farmacologia e Tossicologia, Università degli Studi di Firenze, Viale Pieraccini 6, 50139 Firenze, Italy;1. Department of Cardiology, Acibadem Mehmet Ali Aydinlar University, Faculty of Medicine, Istanbul, Turkey;2. Institute of Health Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey;3. MUHAS Genetics Laboratory, MUHAS, Muhimbili University of Health and Allied Sciences, Dar Es Salaam, Tanzania;4. Department of Cardiovascular Surgery, Istanbul Bilim University, Istanbul, Turkey;5. Department of Radiology, Istanbul Bilim University, Istanbul, Turkey;6. Sisli Florence Nightingale Hospital, Department of Biochemistry, Istanbul, Turkey;7. Department of Biochemistry, Yildiz Technical University, Istanbul, Turkey;8. Department of Medical Genetics, Child Health Institute, Istanbul University, Istanbul, Turkey;1. Dipartimento di NEUROFARBA, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy;2. Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59717, USA;3. Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK;4. Department of Biotechnology and Organic Chemistry, Tomsk Polytechnic University, Tomsk 634050, Russia;5. Department of Chemistry, Altai State Technical University, Barnaul, Russia;6. Institute of Chinese Medical Sciences, University of Macau, Macau |
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| Abstract: | Following on the recent publication of pharmacologically relevant effects, small molecule inhibitors of adipocyte fatty-acid binding protein 4 (FABP4) have attracted high interest. FABP4 is mainly expressed in macrophages and adipose tissue, where it regulates fatty acid storage and lipolysis, being also an important mediator of inflammation. In this regard, FABP4 recently demonstrated an interesting molecular target for the treatment of type 2 diabetes, other metabolic diseases and some type of cancers. In the past years, hundreds of effective FABP4 inhibitors have been synthesized. In this paper, a quantitative structure-activity relationship (QSAR) model has been produced, in order to predict the bioactivity of FABP4 inhibitors. The methodology has been combined with a scaffold-hopping approach, allowing to identify three new molecules that act as effective inhibitors of this protein. These molecules, synthesized and tested for their FABP4 inhibitor activity, showed IC50 values between 3.70 and 5.59 μM, with a high level of agreement with the predicted values. |
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| Keywords: | FABP4 inhibitors aP2 A-FABP 3D-QSAR Scaffold-hopping BMS309403 analogs Thiazole Triazole Forge and Spark software |
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