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Steered molecular dynamics simulation has revealed the mechanism of formate transport via the substrate channel of formate
dehydrogenase. It is shown that the structural organization of the channel promotes the transport of formate anion in spite
of the fact that the channel is too narrow even for such a small molecule. The conformational mobility of Arg284 residue,
one of the residues forming the wall of the substrate channel, provides for the binding and delivery of formate to the active
site. 相似文献
2.
Zakharenko AL Sukhanova MV Khodyreva SN Novikov FN Stroĭlov VS Nilov DK Chilov GG Shviadas VK Lavrik OI 《Molekuliarnaia biologiia》2011,45(3):565-569
A search for poly(ADP-ribose) polymerase-1 inhibitors by virtual screening of a chemical compound database and a subsequent experimental verification of their activities have been done. It was shown that the most efficient method to predict inhibitory properties implies a combinatorial approach joining molecular docking capabilities with structural filtration. Among more than 300000 database chemicals 9 PARP1 inhibitors were revealed; the most active ones, namely: STK031481, STK056130, and STK265022,--displayed biological effect at a micro-molar concentration (IC50 = 2.0 microM, 1.0 microM and 2.6 microM, respectively). 相似文献
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Kurgina Tatyana A. Shram Stanislav I. Kutuzov Mikhail M. Abramova Tatyana V. Shcherbakova Tatyana A. Maltseva Ekaterina A. Poroikov Vladimir V. Lavrik Olga I. vedas Vytas K. Nilov Dmitry K. 《Biochemistry. Biokhimii?a》2022,87(8):823-831
Biochemistry (Moscow) - Previously, we have found that a nucleic acid metabolite, 7-methylguanine (7mGua), produced in the body can have an inhibitory effect on the poly(ADP-ribose) polymerase 1... 相似文献
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Pushkarev Sergey V. Vinnik Valeriia A. Shapovalova Irina V. Švedas Vytas K. Nilov Dmitry K. 《Biochemistry. Biokhimii?a》2022,87(5):443-449
Biochemistry (Moscow) - tRNA-guanine transglycosylase, an enzyme catalyzing replacement of guanine with queuine in human tRNA and participating in the translation mechanism, is involved in the... 相似文献
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Dmitry K. Nilov Ivan G. Shabalin Vladimir O. Popov 《Journal of biomolecular structure & dynamics》2013,31(2):170-179
The formation of the reactive enzyme–substrate complex of formate dehydrogenase has been investigated by molecular dynamics techniques accounting for different conformational states of the enzyme. Simulations revealed that the transport of substrate to the active site through the substrate channel proceeds in the open conformation of enzyme due to the crucial role of the Arg284 residue acting as a vehicle. However, formate binding in the active site of the open conformation leads to the formation of a nonproductive enzyme–substrate complex. The productive Michaelis complex is formed only in the closed enzyme conformation after the substrate and coenzyme have bound, when required rigidity of the binding site and reactive formate orientation due to interactions with Arg284, Asn146, Ile122, and His332 residues is attained. Then, the high occupancy (up to 75%) of the reactive substrate–coenzyme conformation is reached, which was demonstrated by hybrid quantum mechanics/molecular mechanics simulations using various semiempirical Hamiltonians. 相似文献
6.
D. K. Nilov K. I. Yashina I. V. Gushchina A. L. Zakharenko M. V. Sukhanova O. I. Lavrik V. K. Švedas 《Biochemistry. Biokhimii?a》2018,83(2):152-158
We show for the first time that natural 2,5-diketopiperazines (cyclic dipeptides) can suppress the activity of the important anticancer target poly(ADP-ribose)polymerase (PARP). Cyclo(L-Ala-L-Ala) and cyclo(L-Ala-D-Ala) can interact with the key residues of the PARP-1 active site, as demonstrated using docking and molecular dynamics simulations. One of the amide groups of cyclo(L-Ala-L-Ala) and cyclo(L-Ala-D-Ala) forms hydrogen bonds with the Gly863 residue, while the second amide group can form a hydrogen bond with the catalytic residue Glu988, and the side chain can make a hydrophobic contact with Ala898. Newly identified diketopiperazine inhibitors are promising basic structures for the design of more effective inhibitors of PARP family enzymes. The piperazine core with two chiral centers provides many opportunities for structural optimization. 相似文献
7.
Nilov DK Shabalin IG Popov VO Svedas VK 《Journal of biomolecular structure & dynamics》2012,30(2):170-179
The formation of the reactive enzyme-substrate complex of formate dehydrogenase has been investigated by molecular dynamics techniques accounting for different conformational states of the enzyme. Simulations revealed that the transport of substrate to the active site through the substrate channel proceeds in the open conformation of enzyme due to the crucial role of the Arg284 residue acting as a vehicle. However, formate binding in the active site of the open conformation leads to the formation of a nonproductive enzyme-substrate complex. The productive Michaelis complex is formed only in the closed enzyme conformation after the substrate and coenzyme have bound, when required rigidity of the binding site and reactive formate orientation due to interactions with Arg284, Asn146, Ile122, and His332 residues is attained. Then, the high occupancy (up to 75%) of the reactive substrate-coenzyme conformation is reached, which was demonstrated by hybrid quantum mechanics/molecular mechanics simulations using various semiempirical Hamiltonians. 相似文献
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A. L. Zakharenko M. V. Sukhanova S. N. Khodyreva F. N. Novikov V. S. Stroylov D. K. Nilov G. G. Chilov V. K. Svedas O. I. Lavrik 《Molecular Biology》2011,45(3):517-521
A search for poly(ADP-ribose) polymerase-1 inhibitors by virtual screening of a chemical compound database and a subsequent
experimental verification of their activities have been performed. It was shown that the most efficient method to predict
inhibitory properties implies a combinatorial approach joining molecular docking capabilities with structural filtration.
Among more than 300000 low molecular chemical compounds, 9 PARP1 inhibitors were revealed; the most active ones, namely, STK031481,
STK056130, and STK265022, displayed biological effect at a micromolar concentration (IC50 = 2.0, 1.0, and 2.6 μM, respectively). 相似文献
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