Prediction of Novel Anoctamin1 (ANO1) Inhibitors Using 3D-QSAR Pharmacophore Modeling and Molecular Docking

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.

A Molecular Modeling Approach to Identify Novel Inhibitors of the Major Facilitator Superfamily of Efflux Pump Transporters

“…The aromatic component of the small size inhibitor and its conformational pose seem to be important contributors to stabilizing the interaction with the binding core of the NorA protein. The in silico pharmacokinetics and toxicity (Lipinski’s rules of five, PAINS, and ADMET) of the compound were assessed and found to be satisfactory [39]. Furthermore, details of the mode of binding of the new potential inhibitor CID 44330438 to NorA provides new insight into the molecular mechanism of inhibition of MFS efflux pump transporters.…”

The pharmacology of the TMEM16A channel: therapeutic opportunities

“…Notably, small molecules that modulate the TMEM16A channel (Figure 3) have varied chemical structures, possibly reflecting the existence of multiple sites on the channel structure responsible for drug binding. Strategies based on the 3D quantitative structure-activity relationship (QSAR) to predict target-compound interaction [61] may also aid virtual screening and the rational design of selective, high-affinity TMEM16A modulators.…”

“…Contractile cerebral pericytes adjust capillary diameter and cerebral blood flow (CBF) with fine spatial resolution both physiologically and in disease [60,61] (Figure 4). TMEM16A is expressed in rodent [82,88] and human [88] pericytes and participates in the control of cerebral pericyte tone [88].…”

Integration of Ligand-Based and Structure-Based Methods for the Design of Small-Molecule TLR7 Antagonists

“…The resultant pharmacophore was validated to evaluate the quality of the generated model by using cost analysis [59,93], test set analysis, and Fischer's randomization [59,61]. Fixed cost, total cost, and null cost, which were the three significant cost parameters calculated in the bits unit, dictated the quality of the model [94].…”