Molecular Structures of Human Factor Xa Complexed with Ketopiperazine Inhibitors:  Preference for a Neutral Group in the S1 Pocket

Abstract

The structures of the noncovalent complex of human factor Xa (fXa) with four non-peptide inhibitors containing a central sulfonylpiperazinone scaffold have been determined to about 2.1 A resolution. Highly potent fXa inhibitors containing both neutral groups such as chlorobenzothiophene or chlorothiophene and basic groups such as benzamidine were shown to interact in the S1 pocket through the neutral group whereas the S4 pocket is occupied by the basic moiety. The scaffold comprising the sulfonyl keto piperazine moiety might play a pivotal role in the orientation of substituents, since there is a strong hydrogen bond between Gly219 of fXa and the carbonyl oxygen of the piperazine. This unique "reverse" binding mode is heretofore unreported in fXa and shows that electrostatic interactions in the S1 subsite are not an absolute requirement to maintain high affinity. Selectivity against other serine proteases can be readily explained in light of these structural results. It has opened up new prospects for designing fXa inhibitors with increased oral bioavailability.

Structure–Activity Studies in a Family of β‐Hairpin Protein Epitope Mimetic Inhibitors of the p53–HDM2 Protein–Protein Interaction

“…In contrast, several examples of aromatic-Cl bonds pointing toward the faces of aromatic rings in tyrosine residues are known in serine protease-inhibitor complexes. [44][45][46][47][48] Moreover, such interactions apparently occur quite frequently in small-molecule crystal structures. [45] However, the magnitude of any electrostatic interaction could be very sensitive to the distance between the Cl atom and the aromatic ring.…”

“…[44][45][46][47][48] Moreover, such interactions apparently occur quite frequently in small-molecule crystal structures. [45] However, the magnitude of any electrostatic interaction could be very sensitive to the distance between the Cl atom and the aromatic ring. Apart from electrostatic effects, the increase in hydrophobicity arising from the introduction of a chlorine atom at C6 in the indole ring of 78 A should also favor binding in the hydrophobic pocket on HDM2.…”

Cl–π Interactions in Protein–Ligand Complexes

“…However, these interactions are rarely included in the scoring functions for docking programs, because their precise information is not available. We have focused on the Cl -p interaction, which is one of the welldocumented contacts observed in several serine proteases, such as Trypsin [5] and Factor Xa [6], but there has yet to be a comprehensive theoretical study. We describe here precise analyses of the Cl -p interactions of protein -ligand complexes in crystal structures from the PDB, and evaluate this contact using high-level ab initio molecular orbital (MO) calculations.…”

Introduction of Substituents on the 2-Oxo-piperazine Skeleton by [3+2] Cycloaddition and Subsequent Transformation

“…This is also the case for 2-oxo-piperazines and derivatives, which are privileged biologically active scaffolds and promising pharmaceutical target molecules [1]. From a medicinal standpoint the fields of applications are numerous, e. g. 2-oxo-piperazines were successfully investigated as farnesyl-protein transferase inhibitors, fXa inhibitors or non-peptide GPII antagonists [2]. Members of this class of compounds were investigated as nucleoside analogs [3].…”