Development of a cheminformatics platform for selectivity analyses of carbonic anhydrase inhibitors

Giulio Poli,Salvatore Galati,Adriano Martinelli,Claudiu T Supuran,Tiziano Tuccinardi

doi:10.1080/14756366.2019.1705291

Giulio Poli, Salvatore Galati + Show 3 more

Open Access

https://doi.org/10.1080/14756366.2019.1705291

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Abstract

The selectivity for a specific human Carbonic Anhydrase (hCA) isoform is an important property a hCA inhibitor (CAI) should be endowed with, in order to constitute a valuable therapeutic tool for the treatment of a desired pathology. In this context, we developed a chemoinformatic platform that allows the analysis of the structure and selectivity profile of known CAIs reported in literature, with the aim of identifying structural motifs connected to ligand selectivity, thus providing useful guidelines for the design of novel ligands selective for the desired hCA isoform. The platform is able to perform ultrafast structure and selectivity analyses through ligand fingerprint similarity, with no need of structural information about the target receptor and ligands’ binding mode. It is easily accessible to the non-expert user through the implementation of a KNIME Analytic Platform workflow and could be extended to analyze the selectivity profile of known ligands of different target proteins.

Highlights

Human Carbonic Anhydrases (CAs) constitute a superfamily of metalloenzymes characterized by the presence of a zinc (Zn2þ) ion as prosthetic group, which is necessary for their catalytic activity
As a first step in the development of our selectivity analysis platform, we focused on gathering a large amount of bioactivity data related to human Carbonic Anhydrase (hCA) inhibition and the corresponding structures of small-molecule ligands experimentally tested for hCAs inhibitory activity
The 13 final datasets of CA inhibitors (CAIs) were eventually merged into a single database to be used for selectivity profile analyses, including all compounds presenting a Ki value for at least one out of the 13 hCA isoforms considered in this study

Summary

Introduction

Human Carbonic Anhydrases (CAs) constitute a superfamily of metalloenzymes characterized by the presence of a zinc (Zn2þ) ion as prosthetic group, which is necessary for their catalytic activity. Among the six genetic CA families, a-CAs are certainly the most studies enzymes, since they are expressed in humans as in other mammalians and vertebrates; in particular, 16 different human CA isoforms have been identified to date: hCA I–IV, hCA Va, hCA Vb and hCA VI–XV1 These isoforms are characterized by different tissue and subcellular localization and are implied in the plethora of physiological processes in which the synthesis, transport and homeostasis of carbon dioxide play an important role. Due to the many different pathological implications they are involved with and their therapeutic importance, hCAs constitute a well-studied family of drug targets within the medicinal chemistry field. This is proved by the remarkable volume of scientific literature focused on hCAs, counting almost fifteen thousand of research and review articles. We aimed at developing a chemoinformatic platform that could allow a rapid and systematic analysis of the publicly available

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