-
Je něco špatně v tomto záznamu ?
Advances in Structural Biology of ACE and Development of Domain Selective ACE-inhibitors
M. Polakovičová, J. Jampílek,
Jazyk angličtina Země Nizozemsko
Typ dokumentu časopisecké články, přehledy
- MeSH
- angiotensin konvertující enzym chemie metabolismus MeSH
- inhibitory ACE chemie metabolismus MeSH
- katalytická doména MeSH
- krystalografie rentgenová MeSH
- lidé MeSH
- proteinové domény MeSH
- racionální návrh léčiv MeSH
- substrátová specifita MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND: The Angiotensin-I converting enzyme (ACE) is one of the most important components of the renin-angiotensin-aldosterone system controlling blood pressure and renal functions. Inhibitors of ACE are first line therapeutics used in the treatment of hypertension and related cardiovascular diseases. Somatic ACE consists of two homologous catalytic domains, the C- and N-domains. Recent findings have shown that although both domains are highly homologous in structure, they may have different physiological functions. The C-domain is primarily involved in the control of blood pressure, in contrast to the N-domain that is engaged in the regulation of hematopoietic stem cell proliferation. The currently available ACE inhibitors have some adverse effects that can be attributed to the non-selective inhibition of both domains. In addition, specific Ndomain inhibitors have emerged as potential antifibrotic drugs. Therefore, ACE is still an important drug target for the development of novel domain-selective drugs not only for the cardiovascular system but also for other systems. OBJECTIVE: Detailed structural information about interactions in the protein-ligand complex is crucial for rational drug design. This review highlights the structural information available from crystallographic data which is essential for the development of domain selective inhibitors of ACE. METHODS: Over eighty crystal complexes of ACE are placed into the Protein Database. An overview of X-ray ACE complexes with various inhibitors in C- and N-domains and an analysis of their binding mode have given mechanistic explanation of the structural determinants of selective ligand binding. In addition, ACE domain selective inhibitors with dual modes of action in complexes with ACE are also discussed. CONCLUSION: Selectivity of ACE inhibitors for the N- and C-domain is controlled by subtle differences in the amino-acids forming the active site. Reported studies of crystal complexes of inhibitors in the C- and N-domains revealed that most selective inhibitors interact with non-conserved amino-acids between domains and have distinct interactions with the residues in the S2 and S2' subsites of the ACE catalytic site. Moreover, unusual binding of the second molecule of inhibitors in the binding cavity opens new possibilities of exploiting more distant regions of the catalytic center in structure-based design of novel drugs.
Citace poskytuje Crossref.org
- 000
- 00000naa a2200000 a 4500
- 001
- bmc19044833
- 003
- CZ-PrNML
- 005
- 20200115131326.0
- 007
- ta
- 008
- 200109s2019 ne f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.2174/1573406415666190514081132 $2 doi
- 035 __
- $a (PubMed)31084594
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a ne
- 100 1_
- $a Polakovičová, Mája $u Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University in Bratislava, Odbojarov 10, SK-83232 Bratislava, Slovakia.
- 245 10
- $a Advances in Structural Biology of ACE and Development of Domain Selective ACE-inhibitors / $c M. Polakovičová, J. Jampílek,
- 520 9_
- $a BACKGROUND: The Angiotensin-I converting enzyme (ACE) is one of the most important components of the renin-angiotensin-aldosterone system controlling blood pressure and renal functions. Inhibitors of ACE are first line therapeutics used in the treatment of hypertension and related cardiovascular diseases. Somatic ACE consists of two homologous catalytic domains, the C- and N-domains. Recent findings have shown that although both domains are highly homologous in structure, they may have different physiological functions. The C-domain is primarily involved in the control of blood pressure, in contrast to the N-domain that is engaged in the regulation of hematopoietic stem cell proliferation. The currently available ACE inhibitors have some adverse effects that can be attributed to the non-selective inhibition of both domains. In addition, specific Ndomain inhibitors have emerged as potential antifibrotic drugs. Therefore, ACE is still an important drug target for the development of novel domain-selective drugs not only for the cardiovascular system but also for other systems. OBJECTIVE: Detailed structural information about interactions in the protein-ligand complex is crucial for rational drug design. This review highlights the structural information available from crystallographic data which is essential for the development of domain selective inhibitors of ACE. METHODS: Over eighty crystal complexes of ACE are placed into the Protein Database. An overview of X-ray ACE complexes with various inhibitors in C- and N-domains and an analysis of their binding mode have given mechanistic explanation of the structural determinants of selective ligand binding. In addition, ACE domain selective inhibitors with dual modes of action in complexes with ACE are also discussed. CONCLUSION: Selectivity of ACE inhibitors for the N- and C-domain is controlled by subtle differences in the amino-acids forming the active site. Reported studies of crystal complexes of inhibitors in the C- and N-domains revealed that most selective inhibitors interact with non-conserved amino-acids between domains and have distinct interactions with the residues in the S2 and S2' subsites of the ACE catalytic site. Moreover, unusual binding of the second molecule of inhibitors in the binding cavity opens new possibilities of exploiting more distant regions of the catalytic center in structure-based design of novel drugs.
- 650 _2
- $a inhibitory ACE $x chemie $x metabolismus $7 D000806
- 650 _2
- $a zvířata $7 D000818
- 650 _2
- $a katalytická doména $7 D020134
- 650 _2
- $a krystalografie rentgenová $7 D018360
- 650 _2
- $a racionální návrh léčiv $7 D015195
- 650 _2
- $a lidé $7 D006801
- 650 _2
- $a angiotensin konvertující enzym $x chemie $x metabolismus $7 D007703
- 650 _2
- $a vazba proteinů $7 D011485
- 650 _2
- $a proteinové domény $7 D000072417
- 650 _2
- $a substrátová specifita $7 D013379
- 655 _2
- $a časopisecké články $7 D016428
- 655 _2
- $a přehledy $7 D016454
- 700 1_
- $a Jampílek, Josef $u Division of Biologically Active Complexes and Molecular Magnets, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University Olomouc, Slechtitelu 27, CZ-78371 Olomouc, Czech Republic. Department of Analytical Chemistry, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, SK-84215 Bratislava, Slovakia.
- 773 0_
- $w MED00180387 $t Medicinal chemistry (Shariqah (United Arab Emirates)) $x 1875-6638 $g Roč. 15, č. 6 (2019), s. 574-587
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/31084594 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y a $z 0
- 990 __
- $a 20200109 $b ABA008
- 991 __
- $a 20200115131659 $b ABA008
- 999 __
- $a ok $b bmc $g 1483102 $s 1083506
- BAS __
- $a 3
- BAS __
- $a PreBMC
- BMC __
- $a 2019 $b 15 $c 6 $d 574-587 $e - $i 1875-6638 $m Medicinal chemistry $n Med Chem $x MED00180387
- LZP __
- $a Pubmed-20200109