Abstract
We report the design and synthesis of a series of dipeptide-type inhibitors with novel P3 scaffolds that display potent inhibitory activity against SARS-CoV 3CLpro. A docking study involving binding between the dipeptidic lead compound 4 and 3CLpro suggested the modification of a structurally flexible P3 N-(3-methoxyphenyl)glycine with various rigid P3 moieties in 4. The modifications led to the identification of several potent derivatives, including 5c-k and 5n with the inhibitory activities (Ki or IC50) in the submicromolar to nanomolar range. Compound 5h, in particular, displayed the most potent inhibitory activity, with a Ki value of 0.006 μM. This potency was 65-fold higher than the potency of the lead compound 4 (Ki = 0.39 μM). In addition, the Ki value of 5h was in very good agreement with the binding affinity (16 nM) observed in isothermal titration calorimetry (ITC). A SAR study around the P3 group in the lead 4 led to the identification of a rigid indole-2-carbonyl unit as one of the best P3 moieties (5c). Further optimization showed that a methoxy substitution at the 4-position on the indole unit was highly favorable for enhancing the inhibitory potency.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 372-384 |
| Number of pages | 13 |
| Journal | European Journal of Medicinal Chemistry |
| Volume | 68 |
| DOIs | |
| State | Published - 2013 |
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Keywords
- Cysteine protease inhibitors
- Dipeptide
- Peptidomimetics
- SARS
ASJC Scopus subject areas
- Drug Discovery
- Organic Chemistry
- Pharmacology
Cite this
Development of potent dipeptide-type SARS-CoV 3CL protease inhibitors with novel P3 scaffolds : Design, synthesis, biological evaluation, and docking studies. / Thanigaimalai, Pillaiyar; Konno, Sho; Yamamoto, Takehito; Koiwai, Yuji; Taguchi, Akihiro; Takayama, Kentaro; Yakushiji, Fumika; Akaji, Kenichi; Chen, Shen En; Naser-Tavakolian, Aurash; Schön, Arne; Freire, Ernesto I; Hayashi, Yoshio.
In: European Journal of Medicinal Chemistry, Vol. 68, 2013, p. 372-384.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Development of potent dipeptide-type SARS-CoV 3CL protease inhibitors with novel P3 scaffolds
T2 - Design, synthesis, biological evaluation, and docking studies
AU - Thanigaimalai, Pillaiyar
AU - Konno, Sho
AU - Yamamoto, Takehito
AU - Koiwai, Yuji
AU - Taguchi, Akihiro
AU - Takayama, Kentaro
AU - Yakushiji, Fumika
AU - Akaji, Kenichi
AU - Chen, Shen En
AU - Naser-Tavakolian, Aurash
AU - Schön, Arne
AU - Freire, Ernesto I
AU - Hayashi, Yoshio
PY - 2013
Y1 - 2013
N2 - We report the design and synthesis of a series of dipeptide-type inhibitors with novel P3 scaffolds that display potent inhibitory activity against SARS-CoV 3CLpro. A docking study involving binding between the dipeptidic lead compound 4 and 3CLpro suggested the modification of a structurally flexible P3 N-(3-methoxyphenyl)glycine with various rigid P3 moieties in 4. The modifications led to the identification of several potent derivatives, including 5c-k and 5n with the inhibitory activities (Ki or IC50) in the submicromolar to nanomolar range. Compound 5h, in particular, displayed the most potent inhibitory activity, with a Ki value of 0.006 μM. This potency was 65-fold higher than the potency of the lead compound 4 (Ki = 0.39 μM). In addition, the Ki value of 5h was in very good agreement with the binding affinity (16 nM) observed in isothermal titration calorimetry (ITC). A SAR study around the P3 group in the lead 4 led to the identification of a rigid indole-2-carbonyl unit as one of the best P3 moieties (5c). Further optimization showed that a methoxy substitution at the 4-position on the indole unit was highly favorable for enhancing the inhibitory potency.
AB - We report the design and synthesis of a series of dipeptide-type inhibitors with novel P3 scaffolds that display potent inhibitory activity against SARS-CoV 3CLpro. A docking study involving binding between the dipeptidic lead compound 4 and 3CLpro suggested the modification of a structurally flexible P3 N-(3-methoxyphenyl)glycine with various rigid P3 moieties in 4. The modifications led to the identification of several potent derivatives, including 5c-k and 5n with the inhibitory activities (Ki or IC50) in the submicromolar to nanomolar range. Compound 5h, in particular, displayed the most potent inhibitory activity, with a Ki value of 0.006 μM. This potency was 65-fold higher than the potency of the lead compound 4 (Ki = 0.39 μM). In addition, the Ki value of 5h was in very good agreement with the binding affinity (16 nM) observed in isothermal titration calorimetry (ITC). A SAR study around the P3 group in the lead 4 led to the identification of a rigid indole-2-carbonyl unit as one of the best P3 moieties (5c). Further optimization showed that a methoxy substitution at the 4-position on the indole unit was highly favorable for enhancing the inhibitory potency.
KW - Cysteine protease inhibitors
KW - Dipeptide
KW - Peptidomimetics
KW - SARS
UR - http://www.scopus.com/inward/record.url?scp=84882798645&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84882798645&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2013.07.037
DO - 10.1016/j.ejmech.2013.07.037
M3 - Article
C2 - 23994330
AN - SCOPUS:84882798645
VL - 68
SP - 372
EP - 384
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -