本文選題：FabH　切入點(diǎn)：4VM　出處：《天津理工大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：首先,本文分別應(yīng)用分子動力學(xué)模擬實(shí)驗(yàn)及MM-PBSA方法研究了ecFabH單體及4VM類衍生物存在時復(fù)合物體系的RMSD、Rg、RMSF、蛋白二級結(jié)構(gòu)、關(guān)鍵殘基質(zhì)心距及相對結(jié)合自由能隨模擬時間變化規(guī)律。其次,從ChemDiv庫中篩選FabH抑制劑,借助FAF-DRUGS3進(jìn)行ADME/T預(yù)測,采用多種分子對接軟件進(jìn)行結(jié)合能評價,篩選得到35個具有潛在成藥性且結(jié)合能較低的分子,以此總結(jié)出FabH抑制劑應(yīng)有的結(jié)構(gòu)特性。最后,基于本組歷年來合成的數(shù)百個有抗菌生物活性的化合物與FabH進(jìn)行分子對接篩選,選取結(jié)合能較低且結(jié)構(gòu)合適的化合物,基于此新設(shè)計(jì)一系列新型FabH抑制劑并進(jìn)行對接篩選,經(jīng)過進(jìn)一步改造得到目標(biāo)化合物125,并分別選取化合物A6、95、125進(jìn)行分子動力學(xué)模擬實(shí)驗(yàn),研究其微觀作用機(jī)制。分子動力學(xué)研究表明:無抑制劑存在時,FabH單體體系穩(wěn)定性較差,活性口袋殘基波動較大,FabH活性口袋處α螺旋有輕微向外擴(kuò)張趨勢,以便為了底物或配體更好的進(jìn)入。當(dāng)抑制劑4VK、4LB、4VL或4VM存在時,均可使FabH活性口袋入口處α螺旋收緊,從而阻擋底物乙酰-CoA的進(jìn)入,尤其是4VM既可與活性位點(diǎn)殘基形成氫鍵結(jié)合等相互作用,又能很好地占據(jù)本該屬于底物乙酰-CoA的位置,這種“雀占鳩巢”的穩(wěn)定結(jié)合作用,決定了其可作為一個高效的FabH抑制劑。虛擬篩選得到的化合物在結(jié)構(gòu)上有如下特征:抑制劑在活性位點(diǎn)附近的部分,含有氫鍵供體或受體部分,能與FabH酶的活性位點(diǎn)催化三聯(lián)體Cys112-His244-Asn274形成氫鍵作用,相當(dāng)于產(chǎn)生一個“錨”結(jié)構(gòu),將其牢牢固定在催化三聯(lián)體附近,抑制劑的其余部分沿著細(xì)長的活性口袋向外延伸,并可與附近殘基作用,抑制劑末端部分最好也含有氫鍵供體或受體,以便能和通道入口處富含Arg的區(qū)域結(jié)合,從而產(chǎn)生更加緊密的結(jié)合,牢牢占據(jù)活性通道而阻止酶底物乙酰-CoA的進(jìn)入,達(dá)到抑制效果。新設(shè)計(jì)得到的FabH抑制劑125與ecFabH有很高的親和性,分子動力學(xué)模擬實(shí)驗(yàn)證實(shí),發(fā)現(xiàn)FabH活性口袋處殘基Trp32、Ile33、Arg36、Thr37、Ile155、Ile157、Met207、Asn210、Val212、Phe213、Asn247、Phe304在抑制劑結(jié)合中有重要作用,化合物125可很好的與上述殘基形成相互作用,可基于此利用模板定位法、原子生長法及分子碎片法等全新藥物設(shè)計(jì)方法,設(shè)計(jì)出新型FabH抑制劑。
[Abstract]:Firstly, molecular dynamics simulation and MM-PBSA method were used to study the secondary structure of RMSDX RMSF, protein in the complex system of ecFabH monomer and 4VM derivative. The centroid distance of the key residues and the relative binding free energy varied with the simulated time. Secondly, the FabH inhibitors were screened from the ChemDiv library, the ADME/T was predicted by FAF-DRUGS3, and the binding energy was evaluated by a variety of molecular docking software. 35 molecules with potential drug potential and low binding energy were screened to summarize the structural properties of FabH inhibitors. Based on the molecular docking screening of hundreds of antimicrobial bioactive compounds with FabH over the years, a series of novel FabH inhibitors were designed and screened based on the selection of compounds with low binding energy and suitable structure. After further modification, the target compound 125 was obtained, and the molecular dynamics simulation experiment was carried out on the compound A6O95H125.The molecular dynamics study showed that the stability of the monomers of Fabh was poor when there was no inhibitor. The residue of active pocket fluctuates greatly. The 偽 helix in the active pocket of Fabh has a slight outward expansion trend in order to better enter the substrate or ligand. The 偽 helix at the entrance of the active pocket of FabH can be tightened when the inhibitor 4VKO 4LBN 4VL or 4VM exists. Thus blocking the entry of substrate acetyl-CoA, especially 4VM can not only form hydrogen bond binding with active site residues, but also occupy the position that belongs to substrate acetyl-CoA. It is determined that it can be used as an efficient FabH inhibitor. The compounds obtained by virtual screening have the following structural characteristics: the inhibitor is located near the active site and contains the hydrogen bond donor or receptor part. It can catalyze the hydrogen bond formation of triplet Cys112-His244-Asn274 with the active site of FabH enzyme, which is equivalent to producing an "anchor" structure, which is firmly immobilized near the catalytic triad, and the rest of the inhibitor extends outward along the slender active pocket. And can interact with nearby residues, and the end of the inhibitor preferably also contains a hydrogen bond donor or receptor to bind to a region rich in Arg at the entrance of the channel, resulting in closer binding. The new FabH inhibitor 125 has high affinity to ecFabH, which is confirmed by molecular dynamics simulation. It was found that the residue of Trp32AIle3C3HN Arg36Th r37C Ile155H Met207Asn210AV 212Phe213Asn247Phe304 plays an important role in inhibitor binding. Compound 125 can interact well with the above residues, which can be used to design new drugs, such as template localization method, atomic growth method and molecular fragment method. A new type of FabH inhibitor was designed.
【學(xué)位授予單位】：天津理工大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R91

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本文編號：1621555