3D-QSAR assisted identification of FABP4 inhibitors: An effective scaffold hopping analysis/QSAR evaluation

Giuseppe Floresta; Agostino Cilibrizzi; Vincenzo Abbate; Ambra Spampinato; Chiara Zagni; Antonio Rescifina

doi:10.1016/j.bioorg.2018.11.045

3D-QSAR assisted identification of FABP4 inhibitors: An effective scaffold hopping analysis/QSAR evaluation

Bioorg Chem. 2019 Mar:84:276-284. doi: 10.1016/j.bioorg.2018.11.045. Epub 2018 Nov 29.

Authors

Giuseppe Floresta¹, Agostino Cilibrizzi², Vincenzo Abbate³, Ambra Spampinato⁴, Chiara Zagni⁴, Antonio Rescifina⁵

Affiliations

¹ Department of Drug Sciences, University of Catania, V.le A. Doria 6, 95125 Catania, Italy; Department of Chemical Sciences, University of Catania, V.le A. Doria, 95125 Catania, Italy; Institute of Pharmaceutical Science, King's College London, Stamford Street, London SE1 9NH, UK. Electronic address: giuseppe.floresta@unict.it.
² Institute of Pharmaceutical Science, King's College London, Stamford Street, London SE1 9NH, UK; King's Forensics, School of Population Health & Environmental Sciences, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
³ King's Forensics, School of Population Health & Environmental Sciences, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
⁴ Department of Drug Sciences, University of Catania, V.le A. Doria 6, 95125 Catania, Italy.
⁵ Department of Drug Sciences, University of Catania, V.le A. Doria 6, 95125 Catania, Italy. Electronic address: arescifina@unict.it.

PMID: 30529845
DOI: 10.1016/j.bioorg.2018.11.045

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.

Keywords: 3D-QSAR; A-FABP; BMS309403 analogs; FABP4 inhibitors; Forge and Spark software; Scaffold-hopping; Thiazole; Triazole; aP2.

MeSH terms

Fatty Acid-Binding Proteins / antagonists & inhibitors*
Fatty Acid-Binding Proteins / metabolism
Humans
Hypoglycemic Agents / chemical synthesis
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / metabolism
Imidazoles / chemical synthesis
Imidazoles / chemistry
Imidazoles / metabolism
Models, Molecular
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / metabolism
Quantitative Structure-Activity Relationship*
Thiophenes / chemical synthesis
Thiophenes / chemistry
Thiophenes / metabolism

Substances

FABP4 protein, human
Fatty Acid-Binding Proteins
Hypoglycemic Agents
Imidazoles
Pyrazoles
Thiophenes