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

Giuseppe Floresta^*, Agostino Cilibrizzi, Vincenzo Abbate, Ambra Spampinato, Chiara Zagni, Antonio Rescifina

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	276-284
Number of pages	9
Journal	BIOORGANIC CHEMISTRY
Volume	84
Early online date	29 Nov 2018
DOIs	https://doi.org/10.1016/j.bioorg.2018.11.045
Publication status	Published - 1 Mar 2019

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bioorg.2018.11.045

3D-QSAR assisted identification_FLORESTA_Firstonline29November2018_GREEN AAM (CC BY-NC-ND)Accepted author manuscript, 1.08 MBLicence: CC BY-NC-ND

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

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, aP2, BMS309403 analogs, FABP4 inhibitors, Forge and Spark software, Scaffold-hopping, Thiazole, Triazole",

author = "Giuseppe Floresta and Agostino Cilibrizzi and Vincenzo Abbate and Ambra Spampinato and Chiara Zagni and Antonio Rescifina",

year = "2019",

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doi = "10.1016/j.bioorg.2018.11.045",

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T2 - An effective scaffold hopping analysis/QSAR evaluation

AU - Floresta, Giuseppe

AU - Cilibrizzi, Agostino

AU - Abbate, Vincenzo

AU - Spampinato, Ambra

AU - Zagni, Chiara

AU - Rescifina, Antonio

PY - 2019/3/1

Y1 - 2019/3/1

N2 - 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.

AB - 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.

KW - 3D-QSAR

KW - A-FABP

KW - aP2

KW - BMS309403 analogs

KW - FABP4 inhibitors

KW - Forge and Spark software

KW - Scaffold-hopping

KW - Thiazole

KW - Triazole

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DO - 10.1016/j.bioorg.2018.11.045

M3 - Article

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VL - 84

SP - 276

EP - 284

JO - BIOORGANIC CHEMISTRY

JF - BIOORGANIC CHEMISTRY

ER -

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

Abstract

Keywords

UN SDGs

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