Quantum chemical study of silanediols as metal binding groups for metalloprotease inhibitors

• Published in: Journal of molecular modeling Vol. 19; no. 4; pp. 1819 - 1834
• Main Authors: Ignatyev, Igor S., Montejo, Manuel, Rodríguez Ortega, Pilar Gema, González, Juan Jesús López
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-04-2013
• Subjects: Ammonia - chemistry; Binding Sites; Characterization and Evaluation of Materials; Chemistry; Chemistry and Materials Science; Computer Appl. in Life Sciences; Computer Applications in Chemistry; Coordination Complexes - chemistry; Humans; Hydroxamic Acids - chemistry; Imidazoles - chemistry; Iron - chemistry; Kinetics; Metalloproteases - antagonists & inhibitors; Metalloproteases - chemistry; Models, Chemical; Molecular Medicine; Nickel - chemistry; Organosilicon Compounds - chemistry; Original Paper; Protease Inhibitors - chemistry; Protein Binding; Silanes - chemistry; Theoretical and Computational Chemistry; Thermodynamics; Water; Zinc - chemistry; Metal binding groups; Silanediol functionality; DFT; Metalloproteases inhibitors; Binding energy
• ISSN: 1610-2940; 0948-5023
• DOI: 10.1007/s00894-012-1745-0

DFT (B3LYP and M06L) as well as
ab initio
(MP2) methods with Dunning cc-pVnZ (
n
 = 2,3) basis sets are employed for the study of the binding ability of the new class of protease inhibitors, i.e., silanediols, in comparison to the well-known and well-studied class of inhibitors with hydroxamic functionality (HAM). Active sites of metalloproteases are modeled by [R
3
M-OH
2
]
2+
complexes, where R stands for ammonia or imidazole molecules and M is a divalent cation, namely zinc, iron or nickel (in their different spin states). The inhibiting activity is estimated by calculating Gibbs free energies of the water displacement by metal binding groups (MBGs) according to: [R
3
M-OH
2
]
2+
+ MBG → [R
3
M-MBG]
2+
+ H
2
O. The binding energy of silanediol is only a few kcal mol
−1
inferior to that of HAM for zinc and iron complexes and is even slightly higher for the triplet state of the (NH
3
)
3
Ni
2+
complex. For both MBGs studied in the ammonia model the binding ability is nearly the same, i.e., Fe
2+
(t) > Ni
2+
(t) > Fe
2+
(q) > Ni
2+
(s) > Zn
2+
. However, for the imidazole model the order is slightly different, i.e., Ni
2+
(t) > Fe
2+
(t) > Fe
2+
(q) > Ni
2+
(s) ≥ Zn
2+
. Equilibrium structures of the R
3
Zn
2+
complexes with both HAM and silanediol are characterized by the monodentate binding, but the bidentate character of binding increases on going to iron and nickel complexes. Two types of intermediates of the water displacement reactions for [(NH
3
)
3
M-OH
2
]
2+
complexes were found which differ by the direction of the attack of the MBG. Hexacoordinated complexes exhibit bidentate bonding of MBGs and are lower in energy for M=Ni and Fe. For Zn penta- and hexacoordinated complexes have nearly the same energy. Intermediate complexes with imidazole ligands have only octahedral structures with bidentate bonding of both HAM and dimethylsilanediol molecules.