Fragment Growing to Design Optimized Inhibitors for Human Blood Group B Galactosyltransferase (GTB)

Abstract

Human blood group B galactosyltransferase (GTB) catalyzes the galactosylation of the H antigen and is responsible for the formation of the blood group antigen of phenotype B. The ABO blood group system is well studied and routinely serotyped before transfusion and transplantation. Blood type subgroups have been repeatedly linked to an increased occurrence of diseases (e.g., a highly increased incidence rate for pancreatic cancer for individuals with blood group phenotype B). 3‐Phenyl‐5‐(piperazin‐1‐yl)‐1,2,4‐thiadiazole 1 has previously been described to inhibit GTB with a Ki value of 800 μm. In this work, we describe a computer‐guided fragment‐growing approach for the optimization of this fragment that was subsequently realized by synthesizing the most promising ligands. Enlarging the phenyl moiety of fragment 1 to a naphthyl moiety resulted in ligand 3‐(naphthalene‐1‐yl)‐5‐(piperazin‐1‐yl)‐1,2,4‐thiadiazole 2 a, which shows a threefold improvement in binding affinity (Ki=271 μm).

In silico Strategies to Support Fragment-to-Lead Optimization in Drug Discovery

“…A recent paper published by Strecker et al (2019) is an example of how the growing strategy can be used to improve bind affinity. Using computer-aided drug design (CADD) and synthesis, the authors explored small structural modifications in a previously (PDB: 3U0X) identified compound (1) (K i = 800 µM).…”

Novel benzenesulfonamide‐bearing pyrazoles and 1,2,4‐thiadiazoles as selective carbonic anhydrase inhibitors

“…However, our efforts to synthesize thioureido‐linked isoxazoles 9 led to the formation of amino‐1,2,4‐thiadiazoles 10 as the final product in place of the anticipated isoxazoles 9 . Further, a literature survey revealed that the 1,2,4‐thiadiazole moiety has significant medicinal applications [ 42–46 ] and can be investigated as a potent pharmacological candidate. Therefore, to investigate the CA inhibition profile of amino‐1,2,4‐thiadiazoles 10 and to compare the results with thioureido‐linked pyrazoles 8 , a total of 20 derivatives were synthesized from both series in this study.…”