Abstract
Consumption has been a scourge of mankind since ancient times. This illness has charged a high price to human lives. Many efforts have been made to defeat Mycobacterium tuberculosis (Mt). The M. tuberculosis purine nucleoside phosphorylase (MtPNP) is considered an interesting target to pursuit new potential inhibitors, inasmuch it belongs to the purine salvage pathway and its activity might be involved in the mycobacterial latency process. Here we present the MtPNP crystallographic structure associated with acyclovir and phosphate (MtPNP:ACY:PO 4) at 2.10 resolution. Molecular dynamics simulations were carried out in order to dissect MtPNP:ACY:PO 4 structural features, and the influence of the ligand in the binding pocket stability. Our results revealed that the ligand leads to active site lost of stability, in agreement with experimental results, which demonstrate a considerable inhibitory activity against MtPNP (K i = 150 nM). Furthermore, we observed that some residues which are important in the proper ligand's anchor into the human homologous enzyme do not present the same importance to MtPNP. Therewithal, these findings contribute to the search of new specific inhibitors for MtPNP, since peculiarities between the mycobacterial and human enzyme binding sites have been identified, making a structural-based drug design feasible.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 155-165 |
| Number of pages | 11 |
| Journal | Biochimie |
| Volume | 94 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2012 |
| Externally published | Yes |
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Keywords
- Acyclovir
- Crystallographic structure
- Molecular dynamics
- Mycobacterium tuberculosis
- Purine nucleoside phophorylase
ASJC Scopus subject areas
- Biochemistry
Cite this
Crystal structure and molecular dynamics studies of purine nucleoside phosphorylase from Mycobacterium tuberculosis associated with acyclovir. / Caceres, Rafael A.; Timmers, Luís F S M; Ducati, Rodrigo G.; Da Silva, Diego O N; Basso, Luiz A.; De Azevedo, Walter F.; Santos, Diógenes S.
In: Biochimie, Vol. 94, No. 1, 01.2012, p. 155-165.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Crystal structure and molecular dynamics studies of purine nucleoside phosphorylase from Mycobacterium tuberculosis associated with acyclovir
AU - Caceres, Rafael A.
AU - Timmers, Luís F S M
AU - Ducati, Rodrigo G.
AU - Da Silva, Diego O N
AU - Basso, Luiz A.
AU - De Azevedo, Walter F.
AU - Santos, Diógenes S.
PY - 2012/1
Y1 - 2012/1
N2 - Consumption has been a scourge of mankind since ancient times. This illness has charged a high price to human lives. Many efforts have been made to defeat Mycobacterium tuberculosis (Mt). The M. tuberculosis purine nucleoside phosphorylase (MtPNP) is considered an interesting target to pursuit new potential inhibitors, inasmuch it belongs to the purine salvage pathway and its activity might be involved in the mycobacterial latency process. Here we present the MtPNP crystallographic structure associated with acyclovir and phosphate (MtPNP:ACY:PO 4) at 2.10 resolution. Molecular dynamics simulations were carried out in order to dissect MtPNP:ACY:PO 4 structural features, and the influence of the ligand in the binding pocket stability. Our results revealed that the ligand leads to active site lost of stability, in agreement with experimental results, which demonstrate a considerable inhibitory activity against MtPNP (K i = 150 nM). Furthermore, we observed that some residues which are important in the proper ligand's anchor into the human homologous enzyme do not present the same importance to MtPNP. Therewithal, these findings contribute to the search of new specific inhibitors for MtPNP, since peculiarities between the mycobacterial and human enzyme binding sites have been identified, making a structural-based drug design feasible.
AB - Consumption has been a scourge of mankind since ancient times. This illness has charged a high price to human lives. Many efforts have been made to defeat Mycobacterium tuberculosis (Mt). The M. tuberculosis purine nucleoside phosphorylase (MtPNP) is considered an interesting target to pursuit new potential inhibitors, inasmuch it belongs to the purine salvage pathway and its activity might be involved in the mycobacterial latency process. Here we present the MtPNP crystallographic structure associated with acyclovir and phosphate (MtPNP:ACY:PO 4) at 2.10 resolution. Molecular dynamics simulations were carried out in order to dissect MtPNP:ACY:PO 4 structural features, and the influence of the ligand in the binding pocket stability. Our results revealed that the ligand leads to active site lost of stability, in agreement with experimental results, which demonstrate a considerable inhibitory activity against MtPNP (K i = 150 nM). Furthermore, we observed that some residues which are important in the proper ligand's anchor into the human homologous enzyme do not present the same importance to MtPNP. Therewithal, these findings contribute to the search of new specific inhibitors for MtPNP, since peculiarities between the mycobacterial and human enzyme binding sites have been identified, making a structural-based drug design feasible.
KW - Acyclovir
KW - Crystallographic structure
KW - Molecular dynamics
KW - Mycobacterium tuberculosis
KW - Purine nucleoside phophorylase
UR - http://www.scopus.com/inward/record.url?scp=83555176205&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=83555176205&partnerID=8YFLogxK
U2 - 10.1016/j.biochi.2011.10.003
DO - 10.1016/j.biochi.2011.10.003
M3 - Article
C2 - 22033138
AN - SCOPUS:83555176205
VL - 94
SP - 155
EP - 165
JO - Biochimie
JF - Biochimie
SN - 0300-9084
IS - 1
ER -