Structure-based optimization of potent 4- and 6-azaindole-3-carboxamides as renin inhibitors

Scheiper, Bodo; Matter, Hans; Steinhagen, Henning; Böcskei, Zsolt; Fleury, Valérie; McCort, Gary

doi:10.1016/j.bmcl.2011.06.114

Cited by 25 publications

(22 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…24 independent pH replicas in the pH range 1-9 underwent constant NPT simulations, with an aggregation sampling time of 672 ns. To substantiate the statistical significance of our results, another set of replica-exchange CpHMD simulations was performed starting from the X-ray structure of renin in complex with an inhibitor (PDB: 3sfc 31 ) but with the inhibitor removed. The aggregation sampling time was 648 ns.…”

Section: Resultsmentioning

confidence: 98%

Exploring the pH-dependent structure-dynamics-function relationship of human renin

Henderson

Shen

2020

Preprint

View full text Add to dashboard Cite

Renin is a pepsin-like aspartyl protease and an important drug target for the treatment of hypertension; despite three decades' research, its pH-dependent structure-function relationship remains poorly understood. Here we employed the continuous constant pH molecular dynamics (CpHMD) simulations to decipher the acid/base roles of renin's catalytic dyad and the conformational dynamics of the flap, which is a common structural feature among aspartyl proteases. The calculated pKa's suggest that the catalytic Asp38 and Asp226 serve as the general base and acid, respectively, in agreement with experiment and supporting the hypothesis that renin's neutral optimum pH is due to the substrate-induced pKa shifts of the aspartic dyad. The CpHMD data confirmed our previous hypothesis that hydrogen bond formation is the major determinant of the dyad pKa order. Additionally, our simulations showed that renin's flap remains open regardless of pH, although a Tyr-inhibited state is occasionally formed above pH 5. These findings are discussed in comparison to the related aspartyl proteases, including beta-secretases 1 and 2, capthepsin D, and plasmepsin II. Our work represents a first step towards a systematic understanding of the pH-dependent structure-dynamics-function relationships of pepsin-like aspartyl proteases that play important roles in biology and human disease states.

show abstract

Section: Resultsmentioning

confidence: 98%

Exploring the pH-dependent structure-dynamics-function relationship of human renin

Henderson

Shen

2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Both morpholines ( 1 ) and piperazines ( 2 ) are widely used azaheterocyclic bases in organic synthesis; 1 furthermore, they are a frequently found component in both natural products and pharmaceutical compositions, 1–3 finding applications as key pharmacophores in antidepressants ( 3 ), 4 antibiotics ( 4 ), 5 antipsychotics ( 5 ), 6 anticancer agents ( 6 ) 7 and antihypertensive agents ( 7 ) 8 (Fig. 1).…”

mentioning

confidence: 99%

Enantioselective synthesis of C2-functionalized, N-protected morpholines and orthogonally N,N′-protected piperazines via organocatalysis

O’Reilly

Lindsley

2012

Tetrahedron Letters

View full text Add to dashboard Cite

In this Letter, we describe a novel three-step, one-pot procedure for the enantioselective synthesis of N-benzyl protected morpholines and orthogonally N,N′-protected piperazines with chiral alkyl groups installed at the C2 position of each heterocyclic core via organocatalysis. This methodology allows for the rapid preparation of functionalized morpholines and piperazines that are not readily accessible through any other chemistry in good to excellent % ee (55–98% ee).

show abstract

“…The results of their studies showed that some azaindole derivatives have the potential of intestinal absorption. Therefore, the results of their study can serve as the basis for the initiation of advanced research [59,60].…”

Section: Renin Inhibitorsmentioning

confidence: 99%

Synthetic strategies, SAR studies, and computer modeling of indole 2 and 3-carboxamides as the strong enzyme inhibitors: a review

Chehardoli

Bahmani

2020

Mol Divers

View full text Add to dashboard Cite

Indole derivatives have been the focus of many researchers in the study of pharmaceutical compounds for many years. Researchers have investigated the effect of carboxamide moiety at positions 2 and 3, giving unique inhibitory properties to these compounds. The presence of carboxamide moiety in indole derivatives causes hydrogen bonds with a variety of enzymes and proteins, which in many cases, inhibits their activity. In this review, synthetic strategies of indole 2 and 3-carboxamide derivatives, the type, and mode of interaction of these derivatives against HLGP, HIV-1, renin enzyme, and structure-activity studies of these compounds were investigated. It is hoped that indole scaffolds will be tested in the future for maximum activity in pharmacological compounds.

show abstract

Structure-based optimization of potent 4- and 6-azaindole-3-carboxamides as renin inhibitors

Cited by 25 publications

References 23 publications

Exploring the pH-dependent structure-dynamics-function relationship of human renin

Exploring the pH-dependent structure-dynamics-function relationship of human renin

Enantioselective synthesis of C2-functionalized, N-protected morpholines and orthogonally N,N′-protected piperazines via organocatalysis

Synthetic strategies, SAR studies, and computer modeling of indole 2 and 3-carboxamides as the strong enzyme inhibitors: a review

Contact Info

Product

Resources

About