Heme Oxygenase Database (HemeOxDB) and QSAR Analysis of Isoform 1 Inhibitors

Abstract

Due to increasing interest in the field of heme oxygenases (HOs), we built a ligand database called HemeOxDB that includes the entire set of known HO-1 and HO-2 inhibitors, resulting in more than 400 compounds. The HemeOxDB is available online at http://www.researchdsf.unict.it/hemeoxdb/, and having a robust search engine allows end users to build complex queries, sort tabulated results, and generate color-coded two- and three-dimensional graphs. This database will grow to be a tool for the design of potent and selective HO-1 or HO-2 inhibitors. We were also interested in virtually searching for alternative inhibitors, and, for the first time in the field of HOs, a quantitative structure-activity relationship (QSAR) model was built using half-maximal inhibitory concentration (IC ) values of the whole set of known HO-1 inhibitors, taken from the HemeOxDB and employing the Monte Carlo technique. The statistical quality suggested that the model is robust and possesses desirable predictive potential. The screening of US Food and Drug Administration (FDA)-approved drugs, external to our dataset, suggested new predicted inhibitors, opening the way for replacing imidazole groups. The HemeOxDB and the QSAR model reported herein may help in prospectively identifying or repurposing new drugs with optimal structural attributes for HO enzyme inhibition.

Novel Structural Insight into Inhibitors of Heme Oxygenase-1 (HO-1) by New Imidazole-Based Compounds: Biochemical and In Vitro Anticancer Activity Evaluation

“…Our research interest is related to the development of new antitumor compounds and more specifically selective HO-1 and mixed HO-1/HO-2 inhibitors [ 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. To this extent, we constructed a ligand database with more than 400 molecules (HemeOxDB, ), similar to the one we built for sigma-2 receptor ligands [ 25 , 26 ], that incorporates the entire amount of published HO-1 and HO-2 inhibitors [ 27 , 28 ]. Recently, we reported on a novel class of HO-1 selective and HO-1/HO-2 mixed inhibitors characterized by a phenylethanolic chain linking an imidazole ring to different hydrophobic residues obtained by potholing of the hydrophobic HO-1 western region ( Figure 2 , General Formula) [ 21 ].…”

Fourfold Filtered Statistical/Computational Approach for the Identification of Imidazole Compounds as HO-1 Inhibitors from Natural Products

“…In silico studies represent a convenient and efficient avenue to the identification of new scaffolds and new bioactive compounds with significant savings of time and money. In agreement with our growing interest in developing selective and potent HO-1 inhibitor and driven by the need of identifying new scaffolds endowed with HO-1 activity and selectivity, we recently reported 2D– and 3D–QSAR models based on the whole collection of HO-1 and HO-2 inhibitors reported so far and collected in a database previously built by our research group (HemeOxDB, ) [29,30,31,32,33,34]. Also, scaffold hopping analysis allowed to design and synthesize new potent HO-1 inhibitors characterized by a novel chemotype obtained by modifying the central region of the ligands [35].…”

“…Then the molecules were filtered through a statistical/2D descriptors filters. To perform this, we analyzed the most potent and selective compounds present in the HemeOxDB [31] retrieving only the molecules presenting an HO-1 IC 50 value ≤10 μM and an HO-1/HO-2 selectivity ≥10, for a total of 62 entities. The ranges of Molecular weight (200/535), cLogP (–0.35/5.4), cLogS (–5.90/–0.85), H-acceptors (2/8), H-donor (0/1), Druglikeness (–13.20/8.2), DrugScore (0.12/0.96), Total Surface Area (164/390), Relative PSA (0.085/0.35), and Polar Surface Area (18/90) belonging to the 62 potent and selective compounds were all chosen as 2D descriptors and the dataset of 1,091 molecules was further filtered using these interval values to give eight molecules from the MNP, 47 from the ZNP and 89 from the SN2, for a total of 144 molecules (Supplementary Table S1).…”

A Structure- and Ligand-Based Virtual Screening of a Database of “Small” Marine Natural Products for the Identification of “Blue” Sigma-2 Receptor Ligands

“…The BDB was filtered through an in-house hybrid σ 2 receptor affinity filter [ 30 ], returning for each chemical entity a predicted σ 2 receptor p K i . This 2D-QSAR model [ 30 , 31 ] has been built by using a Monte Carlo-based QSAR analysis employing the software CORAL (version 2016, ) [ 43 , 44 ]. CORAL allows for a hybrid representation of molecular structures that includes a simplified molecular input line entry system (SMILES) and a molecular graph.…”