Flap-site Fragment Restores Back Wild-type Behaviour in Resistant Form of HIV Protease.
Flap-site Fragment Restores Back Wild-type Behaviour in Resistant Form of HIV Protease.
复制标题
瓣位点碎片以抗HIV蛋白酶的抗性形式恢复野生型行为。
DOI：
10.1002/minf.201800053
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发表时间：
2018-12
影响因子：
3.6
通讯作者：
Peruchena N
中科院分区：
文献类型：
--
作者：
Luchi A;Angelina E;Bogado L;Forli S;Olson A;Peruchena N
HIV-1 protease (HIV-PR) performs a vital step in the virus life cycle which makes it an excellent target for drug therapy. However, due to the error-prone of HIV reverse transcriptase, mutations in HIV-PR often occur, inducing drug-resistance to inhibitors. Some HIV-PR mutations can make the flaps of the enzyme more flexible thus increasing the flaps opening rate and inhibitor releasing. It has been shown that by targeting novel binding sites on HIV-PR with small molecules, it is possible to alter the equilibrium of flap conformational states. A previous fragment-based crystallographic screen have found two novel binding sites for small fragments in the inhibited, closed form of HIV-PR, termed flap and exo sites. While these experiments were performed in wild type HIV-PR, it still remains to be proven whether these small fragments can stabilize the closed conformation of flaps in resistant forms of the enzyme. Here we performed Molecular Dynamics simulations of wild type and mutant form of HIV-PR bound to inhibitor TL-3. Simulations show that on going from wild type to 6X mutant the equilibrium shifts from closed to semi-open conformation of flaps. However, when fragment Br6 is placed at flap site of mutant form, the enzyme is restored back to closed conformation. This finding supports the hypothesis that allosteric inhibitors, together with active site inhibitors could increase the number of point mutations necessary for appreciable clinical resistance to AIDS therapy.
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影响因子：
3
作者：
Perryman AL;Zhang Q;Soutter HH;Rosenfeld R;McRee DE;Olson AJ;Elder JE;Stout CD
通讯作者：
Stout CD
耐药突变对 HIV-1 蛋白酶动态特性的影响以及 Amprenavir 和 Darunavir 的抑制作用。
影响因子：
4.6
作者：
Yu Y;Wang J;Shao Q;Shi J;Zhu W
通讯作者：
Zhu W
影响因子：
5.6
作者：
Heaslet, H;Kutilek, V;Stout, CD
通讯作者：
Stout, CD
影响因子：
4
作者：
Tiefenbrunn, Theresa;Forli, Stefano;Baksh, Michael M.;Chang, Max W.;Happer, Meaghan;Lin, Ying-Chuan;Perryman, Alexander L.;Rhee, Jin-Kyu;Torbett, Bruce E.;Olson, Arthur J.;Elder, John H.;Finn, M. G.;Stout, C. David
通讯作者：
Stout, C. David
影响因子：
5.6
作者：
Andujar, Sebastian A.;Tosso, Rodrigo D.;Enriz, Ricardo D.
通讯作者：
Enriz, Ricardo D.