Interaction Studies between Carbonic Anhydrase and a Sulfonamide Inhibitor by Experimental and Theoretical Approaches

Abstract

The most used approaches in structure-based drug design possess peculiar characteristics with advantages and limitations, and thus the management of complementary data from various techniques is of particular interest to synergistically achieve the development of effective enzyme inhibitors. In this Letter, we describe the application of experimental and computational techniques to study the interactions between human carbonic anhydrases and sulfonamide inhibitors. In particular, a series of affinity-labeled carbonic anhydrase inhibitors containing sulfonamido photoprobes was designed and synthesized, and one of these compounds, a benzophenone derivative, was chosen as a model photoprobe/inhibitor. A photoaffinity labeling method followed by mass spectrometry analysis was then applied to elucidate the inhibitor binding site, and a comparison with X-ray crystallography and molecular dynamics simulation data was carried out, highlighting that to have a comprehensive view of the protein/inhibitor complex stabilization all three kinds of experiments are necessary.

Compositional Deep Probabilistic Models of DNA-Encoded Libraries

“…Studies have shown that the benzenesulfonamide substituted at the para position is much more highly active, in general, toward CA-IX protein. 20 Meanwhile, HRP is an enzyme with high affinity for compounds containing sulfonyl chloride-derived Michael acceptors. 9,21 In this data set, there are three such synthons at the B position that show high activity and are the three synthons we treat as "gold" labels for HRP.…”

“…In this data set, there are two synthons at the C position that include benzene-sulfonamides, one that is meta-substituted with respect to the aryl group, and the other which is para-substituted. Studies have shown that the benzene-sulfonamide substituted at the para position is much more highly active, in general, toward CA-IX protein . Meanwhile, HRP is an enzyme with high affinity for compounds containing sulfonyl chloride-derived Michael acceptors. , In this data set, there are three such synthons at the B position that show high activity and are the three synthons we treat as “gold” labels for HRP.…”

Fused Tetrahydroquinolines Are Interfering with Your Assay

“…That both solved structures of bound fused THQs bear electron-withdrawing substituents is coincidental and unlikely to confer added stability to the scaffold. In carbonic anhydrase 2, the primary sulfonamide provides the key pharmacophore for molecular recognition by the enzyme. − The following sections review many papers that have identified fused THQs as hits from high-throughput campaigns (Figure ). While their activities are modest (in the micromolar range), it is striking that additional cocrystal structures have not been solved.…”

Discovery of a New Class of 1-(4-Sulfamoylbenzoyl)piperidine-4-carboxamides as Human Carbonic Anhydrase Inhibitors

“…Regarding derivative 15 , during the MD simulation the carbonyl group linked to the piperidine ring is able to reach Q92, forming a H-bond. (Figure B) The 2-methyl­benzyl­amine moiety moves toward V135, which establishes hydrophobic contacts with the inhibitor, causing the loss of the H-bond with P201 observed in the starting complex (Figure B) …”

“…The distance between the NH − of the sulfonamide moiety and the Zn 2+ ion was monitored along the trajectories yielding values of ∼2 Å, in good agreement with the literature. 26 Clustering analysis was carried out to obtain representative conformations of the systems. The representative structures of the most populated clusters of each simulated system are displayed in Figures 4 and 5.…”