Guyan Liang

Human kallikrein 6 inhibitors with a para-amidobenzylanmine P1 group identified through virtual screening.

A series of hK6 inhibitors with a para-amidobenzylamine P1 group and a 2-hydroxybenzamide scaffold linker was discovered through virtual screening. The X-ray structure of hK6 complexed with compound 9b was determined to a resolution of 1.68Å. The tertiary folding of the hK6 complexed with the inhibitor is conserved relative to the structure of the apo-protein, whereas the interaction between hK6 and the inhibitor is consistent with both the SAR and the in silico model used in the virtual screening.

A conformationally constrained inhibitor with an enhanced potency for β-tryptase and stability against semicarbazide-sensitive amine oxidase (SSAO).

A novel β-tryptase inhibitor with a basic benzylamine P1 group, a piperidine-amide linker, and a substituted indole P4 group was discovered. A substitution at 4-indole position was introduced to constrain the conformational flexibility of the inhibitor to the bioactive conformation exhibited by X-ray structures so that entropic penalty was decreased. More importantly, this constrained conformation limited the accessibility of this molecule to anti-targets, especially SSAO, so that an enhanced metabolic profile was achieved.

Structure-based library design and the discovery of a potent and selective mast cell β-tryptase inhibitor as an oral therapeutic agent

A solid phase combinatorial library was designed based on X-ray structures and in-silico models to explore an inducible S4+ pocket, which is formed by a simple side-chain rotation of Tyr95. This inducible S4+ pocket is unique to β-tryptase and does not exist for other trypsin-like serine proteases of interest. Therefore, inhibitors utilizing this pocket have inherent advantages for being selective against other proteases in the same family. A member of this library was found to be a potent and selective β-tryptase inhibitor with a suitable pharmacokinetic profile for further clinical evaluation.

A β-tryptase inhibitor with a tropanylamide scaffold to improve in vitro stability and to lower hERG channel binding affinity.

Tropanylamide was investigated as a possible scaffold for β-tryptase inhibitors with a basic benzylamine P1 group and a substituted thiophene P4 group. Comparing to piperidinylamide, the tropanylamide scaffold is much more rigid, which presents less opportunity for the inhibitor to bind with off-target proteins, such as cytochrome P450, SSAO, and hERG potassium channel. The proposed binding mode was further confirmed by an in-house X-ray structure through co-crystallization.

Structure-based design, synthesis, and profiling of a β-tryptase inhibitor with a spiro-piperidineamide scaffold, benzylamine P1 group, and a substituted indole P4 group

A β-tryptase inhibitor with a basic benzylamine P1 group, a substituted indole P4 group, and a spiro-piperidineamide scaffold linker was designed, synthesized, and tested for its β-tryptase potency and ADMET properties. Comparing to its non-spiro analogs, the inhibitor with a spiro-piperidineamide scaffold demonstrated superior metabolic stability in human liver microsome and against semicarbazide-sensitive amine oxidase (SSAO).

Structure-based design, synthesis, and profiling of potent and selective neuronal nitric oxide synthase (nNOS) inhibitors with an amidinothiophene hydroxypiperidine scaffold

A novel series of nNOS inhibitors with an amidinothiophene-hydroxypiperidine scaffold was designed based on X-ray structures and in-silico models. Three classes of inhibitors with this scaffold were synthesized and tested for their nNOS activity and eNOS selectivity. Compounds with a linear aliphatic amine linker demonstrated a superior property over those with a sulfonamide or an amide-like linker.

Dimerization of β-tryptase inhibitors, does it work for both basic and neutral P1 groups?

The tetrameric folding of β-tryptase and the pair-wise distribution of its substrate binding sites offer a unique opportunity for development of inhibitors that span two adjacent binding sites. A series of dimeric inhibitors with two basic P1 moieties was discovered using this design strategy and exhibited tight-binder characteristics. Using the same strategy, an attempt was made to design and synthesize dimeric inhibitors with two neutral-P1 groups in hope to exploit the dimeric binding mode to achieve a starting point for further optimization. The unsuccessful attempt, however, demonstrated the important role played by Ala190 in neutral-P1 binding and casted further doubt on the possibility of developing neutral-P1 inhibitors for β-tryptase.