- Pro-Soft Val-boroPro: A strategy for enhancing in vivo performance of boronic acid inhibitors of serine proteases
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Val-boroPro, 1, is a potent, but relatively nonspecific inhibitor of the prolyl peptidases. It has antihyperglycemic activity from inhibition of DPPIV but also striking anticancer activity and a toxicity for which the mechanisms are unknown. 1 cyclizes at
- Poplawski, Sarah E.,Lai, Jack H.,Sanford, David G.,Sudmeier, James L.,Wu, Wengen,Bachovchin, William W.
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- Enhancement of hydrophobic interactions and hydrogen bond strength by cooperativity: Synthesis, modeling, and molecular dynamics simulations of a congeneric series of thrombin inhibitors
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Accurately predicting the binding affinity of ligands to their receptors by computational methods is one of the major challenges in structure-based drug design. One of the potentially significant errors in these predictions is the common assumption that the ligand binding affinity contributions of noncovalent interactions are additive. Herein we present data obtained from two separate series of thrombin inhibitors containing hydrophobic side chains of increasing size that bind in the S3 pocket and with, or without, an adjacent amine that engages in a hydrogen bond with Gly 216. The first series of inhibitors has a m-chlorobenzyl moiety binding in the S1 pocket, and the second has a benzamidine moiety. When the adjacent hydrogen bond is present, the enhanced binding affinity per ?2 of hydrophobic contact surface in the S3 pocket improves by 75% and 59%, respectively, over the inhibitors lacking this hydrogen bond. This improvement of the binding affinity per ?2 demonstrates cooperativity between the hydrophobic interaction and the hydrogen bond.
- Muley, Laveena,Baum, Bernhard,Smolinski, Michael,Freindorf, Marek,Heine, Andreas,Klebe, Gerhard,Hangauer, David G.
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supporting information; experimental part
p. 2126 - 2135
(2010/08/19)
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- Design and synthesis of a series of potent and orally bioavailable noncovalent thrombin inhibitors that utilize nonbasic groups in the P1 position
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As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compo
- Tucker, Thomas J.,Brady, Stephen F.,Lumma, William C.,Lewis, S. Dale,Gardell, Stephen J.,Naylor-Olsen, Adel M.,Yan, Youwei,Sisko, Jack T.,Stauffer, Kenneth J.,Lucas, Bobby J.,Lynch, Joseph J.,Cook, Jacquelynn J.,Stranieri, Maria T.,Holahan, Marie A.,Lyle, Elizabeth A.,Baskin, Elizabeth P.,Chen, I.-Wu,Dancheck, Kimberly B.,Krueger, Julie A.,Cooper, Carolyn M.,Vacca, Joseph P.
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p. 3210 - 3219
(2007/10/03)
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