Abstract
Recently, anoctamin1 (ANO1), a calcium-activated chloride channel, has been considered an important drug target, due to its involvement in various physiological functions, as well as its possibility for treatment of cancer, pain, diarrhea, hypertension, and asthma. Although several ANO1 inhibitors have been discovered by high-throughput screening, a discovery of new ANO1 inhibitors is still in the early phase, in terms of their potency and specificity. Moreover, there is no computational model to be able to identify a novel lead candidate of ANO1 inhibitor. Therefore, three-dimensional quantitative structure-activity relationship (3D-QSAR) pharmacophore modeling approach was employed for identifying the essential chemical features to be required in the inhibition of ANO1. The pharmacophore hypothesis 2 (Hypo2) was selected as the best model based on the highest correlation coefficient of prediction on the test set (0.909). Hypo2 comprised a hydrogen bond acceptor, a hydrogen bond donor, a hydrophobic, and a ring aromatic feature with good statistics of the total cost (73.604), the correlation coefficient of the training set (0.969), and the root-mean-square deviation (RMSD) value (0.946). Hypo2 was well assessed by the test set, Fischer randomization, and leave-one-out methods. Virtual screening of the ZINC database with Hypo2 retrieved the 580 drug-like candidates with good potency and ADMET properties. Finally, two compounds were selected as novel lead candidates of ANO1 inhibitor, based on the molecular docking score and the interaction analysis. In this study, the best pharmacophore model, Hypo2, with notable predictive ability was successfully generated, and two potential leads of ANO1 inhibitors were identified. We believe that these compounds and the 3D-QSAR pharmacophore model could contribute to discovering novel and potent ANO1 inhibitors in the future.
Highlights
Anoctamin1 (ANO1/TMEM16A) is a calcium-activated chloride channel (CaCC) that responds to an increase of intracellular Ca2+ concentration [1,2,3]
For identifying the meaningful pharmacophore features from the training set, the Feature mapping of Discovery Studio 3.1 (DS) was carried out, and it resulted in hydrogen bond donor (HBD), hydrogen bond acceptor (HBA), hydrophobic (HY), and ring aromatic (RA) features
A cost analysis was conducted to assess the quality of the generated pharmacophore hypotheses
Summary
Anoctamin (ANO1/TMEM16A) is a calcium-activated chloride channel (CaCC) that responds to an increase of intracellular Ca2+ concentration [1,2,3]. Several ANO1 inhibitors such as CaCCinh-A01 [9], T16inh-A01 [10], MONNA [11], benzbromarone [12], Ani9 [13], tannic acid [14], eugenol [15], luteolin [16], and crofelemer [17] have been discovered from both the chemical and natural product space. Among the natural product inhibitors of ANO1, the crofelemer (previously known as Fulyzaq and as Mytesi) from Napo Pharmaceutical in 2012 is the first FDA-approved drug to be used for anti-human immunodeficiency virus (HIV) associated anti-diarrhea, through targeting the ANO1 [17,18]
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