Limiting the Number of Potential Binding Modes by Introducing Symmetry into Ligands: Structure‐Based Design of Inhibitors for Trypsin‐Like Serine Proteases

Abstract

In the absence of X-ray data, the exploration of compound binding modes continues to be a challenging task. For structure-based design, specific features of active sites in different targets play a major role in rationalizing ligand binding characteristics. For example, dibasic compounds have been reported as potent inhibitors of various trypsin-like serine proteases, the active sites of which contain several binding pockets that can be targeted by cationic moieties. This results in several possible orientations within the active site, complicating the binding mode prediction of such compounds by docking tools. Therefore, we introduced symmetry in bi- and tribasic compounds to reduce conformational space in docking calculations and to simplify binding mode selection by limiting the number of possible pocket occupations. Asymmetric bisbenzamidines were used as starting points for a multistage and structure-guided optimization. A series of 24 final compounds with either two or three benzamidine substructures was ultimately synthesized and evaluated as inhibitors of five serine proteases, leading to potent symmetric inhibitors for the pharmaceutical drug targets matriptase, matriptase-2, thrombin and factor Xa. This study underlines the relevance of ligand symmetry for chemical biology.

A Fluorescent‐Labeled Phosphono Bisbenzguanidine As an Activity‐Based Probe for Matriptase

“…One benzguanidine moiety is very likely to be oriented towards the deep, negatively charged S1 pocket . However, the remaining benzguanidine is either able to address the S3/S4 or the S2 pocket of matriptase . The assembly of our probe was inspired by several potent dibasic matriptase inhibitors, such as peptidic ketobenzothiazoles derived from the natural Arg‐Gln‐Ala‐Arg autoactivation sequence of matriptase, bis‐benzamidines, or sulfonylated 3‐amidinophenylalanine derivatives .…”

“…[25,26] However,t he remaining benzguanidine is either able to address the S3/S4 or the S2 pocket of matriptase. [4,[27][28][29] The assembly of our probe was inspired by several potent dibasic matriptase inhibitors, such as peptidic ketobenzothiazoles derived from the natural Arg-Gln-Ala-Arg autoactivations equence of matriptase, [27,28] bis-benzamidines, [4,29] or sulfonylated 3-amidinophenylalanine derivatives. [30] To achieve covalent interaction, ap hosphonate group was attached.…”

Frontiers in Medicinal Chemistry 2017 in Bern, Switzerland

“…Furthermore, three PhD prizes were awarded by the GDCh and DPhG (Figure ). Norbert Furtmann (University of Bonn) briefly reported his research on the identification of interaction hot spots in structures of drug targets on the basis of 3D activity cliff formation . Patrick Mäder (ETH Zurich) spoke on his research on the synthesis and biological evaluation of two novel classes of anthelmintics against Schistosoma mansori .…”

“…Norbert Furtmann (University of Bonn) briefly reported his research on the identification of interaction hot spots in structures of drug targets on the basis of 3D activity cliff formation. [40] Patrick Mäder (ETH Zurich)s poke on his research on the synthesis and biological evaluation of two novel classes of anthelmintics against Schistosoma mansori. [41] Finally Roman Sommer (University of Saarbrücken) presented his research on non-natural carbohydrate-based inhibitors of the Pseudomonas aeruginosa virulencef actor lectin LecB.…”

3,1-Benzothiazines, 1,4-Benzodioxines and 1,4-Benzoxazines as Inhibitors of Matriptase-2: Outcome of a Focused Screening Approach

“…A preferred P4–P1 substrate sequence (Ile–Arg–Ala–Arg), obtained by a combinatorial approach, confirmed this primary substrate specificity [ 18 ], which is facilitated by the negatively charged aspartyl side chain at the bottom of their S1 pocket, able to interact with positively charged moieties, e.g., of arginine or arginine mimetics. Moreover, the S3/S4 region of matriptase-2 has also been found to be occupied by positively charged ligand moieties [ 18 , 19 , 20 ].…”