基于靶标结构的环肽分子计算设计

doi:10.12211/2096-8280.2023-006

合成生物学 ›› 2023, Vol. 4 ›› Issue (3): 551-570.DOI: 10.12211/2096-8280.2023-006

基于靶标结构的环肽分子计算设计

王凡灏², 来鲁华¹^,²^,³, 张长胜¹^,²

^1.北京大学前沿交叉学科研究院定量生物学中心，北京 100871
^2.北京大学化学与分子工程学院，北京分子科学国家研究中心，北京 100871
^3.北京大学-清华大学生命科学联合中心，北京 100871

收稿日期:2023-01-12 修回日期:2023-02-23 出版日期:2023-06-30 发布日期:2023-07-05
通讯作者: 张长胜
作者简介:王凡灏（1998—），男，博士研究生。研究方向为基于靶标结构的多肽药物分子设计。 E-mail：wangfh2020@stu.pku.edu.cn
张长胜（1981—），男，副研究员。研究方向为蛋白质设计、计算结构生物学。 E-mail：changshengzhang@pku.edu.cn
基金资助:
国家自然科学基金(21977007)

Target structure based computational design of cyclic peptides

Fanhao WANG², Luhua LAI¹^,²^,³, Changsheng ZHANG¹^,²

^1.Center for Quantitative Biology，Academy for Advanced Interdisciplinary Studies，Peking University，Beijing 100871，China
^2.BNLMS，College of Chemistry and Molecular Engineering，Peking University，Beijing 100871，China
^3.Peking -Tsinghua Center for Life Science，Peking University，Beijing 100871，China

Received:2023-01-12 Revised:2023-02-23 Online:2023-06-30 Published:2023-07-05
Contact: Changsheng ZHANG

摘要/Abstract

摘要：

环肽在调控蛋白质-蛋白质相互作用方面具有独特的优势，在新药研发领域受到了越来越多的关注。蛋白质相互作用界面一般较大而平坦，相较于小分子化合物，环肽分子更容易获得与这些靶标位点结合的高亲和力和高特异性。相较于线性多肽或蛋白质，环肽结构一般具有更大的骨架刚性，更难被酶降解，从而在代谢上更稳定，而且环肽更易于通过修饰改造增加跨膜活性，从而结合细胞内的靶标蛋白。结构数据和结构建模方法是开发基于靶标结构计算设计环肽药物的基础。本文分析了蛋白质结构数据库中环肽与靶标蛋白结合情况，介绍了目前环肽构象生成或结构预测的四类主要算法；总结了基于靶标结构计算设计环肽分子的主要方法，包括基于分子对接的虚拟筛选方法、借助于动力学模拟的设计方法、从头生成的设计方法以及具有跨膜活性的环肽设计方法；并展望了数据驱动的机器学习方法在环肽设计领域中的可能应用以及未来环肽药物分子开发的可能方向。

关键词: 环肽, 多肽药物, 多肽设计, 构象生成

Abstract:

Cyclic peptides (macrocycles) possess head-to-tail cyclic or partially cyclized substructures, which have received more and more attention in developing new drugs recently, since they have unique advantages in regulating protein-protein interactions (PPIs). Comparing to small-molecule compounds, it is easier to design cyclic peptide molecules that bind to target sites with high affinity and specificity, due to the broad and flat interfaces of PPIs and their large surfaces. Moreover, cyclic peptides are generally more rigid and difficult for digestion by proteases than their linear counterparts, making them more stable than linear peptides or proteins. Meanwhile, cyclic peptides are easier for modifications to increase transmembrane activity, targeting intracellular proteins through conformation adaptation or chemical modifications. 3D structure data and structure modeling technics are basis for designing structure based cyclic-peptide drugs. In this review, we assess the structures of cyclic peptides and target proteins available in protein structure database (PDB). Then, we review the algorithms of conformation generation or structure prediction for cyclic peptides, including homologous modeling, secondary structure prediction and optimization, backbone torsion sampling, and distance geometry method. We also summarize progress in target structure based computational design for cyclic peptides, including structure-based virtual screening, molecular dynamic simulation aided methods, de novo design algorithms, and the transmembrane cyclic peptide design. However, more generalized structure-based de novo design algorithms remains to be further explored, and methods to adopt unnatural amino acids or chemical modifications are also needs to be developed. It's worth noting that, with the increase of data for cyclic peptide 3D structures, the data-driven machine learning method may provide a more promising solution for improving the efficiency and effectiveness of structure based cyclic peptide de novo design and conformation generation to develop cyclic peptide drugs in the future.

Key words: cyclic peptides, peptide drugs, peptidedesign, conformation generation

中图分类号:

Q816

王凡灏, 来鲁华, 张长胜. 基于靶标结构的环肽分子计算设计[J]. 合成生物学, 2023, 4(3): 551-570.

Fanhao WANG, Luhua LAI, Changsheng ZHANG. Target structure based computational design of cyclic peptides[J]. Synthetic Biology Journal, 2023, 4(3): 551-570.

图/表 7

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名称	结构	功能简介
罗米地辛（Romidepsin）		靶向组蛋白去乙酰化酶，具有抗癌活性，用于治疗T细胞淋巴瘤
伏环孢素（Voclosporin）		靶向钙调神经磷酸酶，用于治疗狼疮性肾炎
齐考诺肽（Ziconotide）		靶向G蛋白偶联受体，N型钙通道的有效和选择性阻滞剂
利那洛肽（Linaclotide）		鸟苷酸环化酶 C(GC-C) 激动剂
普卡那肽（Plecanatide）		鸟苷酸环化酶-C(GC-C)激动剂
帕西瑞肽（Pasireotide）		生长抑素类似物，靶向生长抑素受体，可以提高生长抑素受体的激动剂活性
兰瑞肽（Lanreotide）		生长素抑制剂的第二代类似物，靶向生长抑素受体，活性更高
加压素（Vasopressin）		一种抗利尿激素，靶向血管加压素受体
特利加压素（Terlipressin）		一种人工合成的长效抗利尿激素，靶向血管加压素受体
布美兰肽（Bremelanotide）		黑素皮质素受体的激动剂，主要作用于MC3和MC4受体
赛美拉肽（Setmelanotide）		黑素皮质素受体的激动剂，主要作用于MC4受体
达托霉素（Daptomycin）		一种环状脂肽抗生素，破坏革兰氏阳性菌的细胞壁
特拉万星（Telavancin）		万古霉素的半合成衍生物，抑制革兰氏阳性菌的细胞壁合成
达巴万星（Dalbavancin）		第二代脂糖肽抗生素药物，比万古霉素更有效，也针对细胞壁的生物合成
奥利万星（Oritavancin）		由氯霉素衍生的万古霉素的合成类似物，抑制细菌细胞壁的合成
卡泊芬净（Caspofungin）		靶向1，3-β-葡聚糖合成酶，对侵袭性念珠菌病和其他形式的系统性真菌病有临床疗效
米卡芬净（Micafungin）		靶向1，3-β-葡聚糖合成酶，对侵袭性念珠菌病和其他形式的系统性真菌病有临床疗效
阿尼芬净（Anidulafungin）		靶向1，3-β-葡聚糖合成酶，对侵袭性念珠菌病和其他形式的系统性真菌病有临床疗效

名称	结构	功能简介
罗米地辛（Romidepsin）		靶向组蛋白去乙酰化酶，具有抗癌活性，用于治疗T细胞淋巴瘤
伏环孢素（Voclosporin）		靶向钙调神经磷酸酶，用于治疗狼疮性肾炎
齐考诺肽（Ziconotide）		靶向G蛋白偶联受体，N型钙通道的有效和选择性阻滞剂
利那洛肽（Linaclotide）		鸟苷酸环化酶 C(GC-C) 激动剂
普卡那肽（Plecanatide）		鸟苷酸环化酶-C(GC-C)激动剂
帕西瑞肽（Pasireotide）		生长抑素类似物，靶向生长抑素受体，可以提高生长抑素受体的激动剂活性
兰瑞肽（Lanreotide）		生长素抑制剂的第二代类似物，靶向生长抑素受体，活性更高
加压素（Vasopressin）		一种抗利尿激素，靶向血管加压素受体
特利加压素（Terlipressin）		一种人工合成的长效抗利尿激素，靶向血管加压素受体
布美兰肽（Bremelanotide）		黑素皮质素受体的激动剂，主要作用于MC3和MC4受体
赛美拉肽（Setmelanotide）		黑素皮质素受体的激动剂，主要作用于MC4受体
达托霉素（Daptomycin）		一种环状脂肽抗生素，破坏革兰氏阳性菌的细胞壁
特拉万星（Telavancin）		万古霉素的半合成衍生物，抑制革兰氏阳性菌的细胞壁合成
达巴万星（Dalbavancin）		第二代脂糖肽抗生素药物，比万古霉素更有效，也针对细胞壁的生物合成
奥利万星（Oritavancin）		由氯霉素衍生的万古霉素的合成类似物，抑制细菌细胞壁的合成
卡泊芬净（Caspofungin）		靶向1，3-β-葡聚糖合成酶，对侵袭性念珠菌病和其他形式的系统性真菌病有临床疗效
米卡芬净（Micafungin）		靶向1，3-β-葡聚糖合成酶，对侵袭性念珠菌病和其他形式的系统性真菌病有临床疗效
阿尼芬净（Anidulafungin）		靶向1，3-β-葡聚糖合成酶，对侵袭性念珠菌病和其他形式的系统性真菌病有临床疗效

PDB编号	环肽配体序列	肽链长度	环的大小	环肽功能	靶蛋白界面埋藏面积/Å²	环化类型
1e4w	SHFNEYE	8	8	TGF-α抗原表位类似物，与tAb2抗体结合	381	酰胺键
1sfi	GRCTKSIPPICFPD	14	14	胰蛋白酶抑制剂	612	酰胺键
2axi	PFE[6cw]LDWEFp	10	10	P53-HDM2配体	510	酰胺键
3av9	SAKIDNLD	8	8	HIV整合酶重组抑制剂	397	酰胺键
3ava	ALKIDNLD	8	8	HIV整合酶重组抑制剂	395	酰胺键
3avb	SLKIDNLD	8	8	HIV整合酶重组抑制剂	401	酰胺键
3avf	DLKIDNLD	8	8	HIV整合酶重组抑制剂	418	酰胺键
3avg	ADKIDNLD	8	8	HIV整合酶重组抑制剂	385	酰胺键
3avh	ARKIDNLD	8	8	HIV整合酶重组抑制剂	388	酰胺键
3avi	SLKIDNMD	8	8	HIV整合酶重组抑制剂	432	酰胺键
3avj	ALKIDNMD	8	8	HIV整合酶重组抑制剂	437	酰胺键
3avk	SLKIDNED	8	8	HIV整合酶重组抑制剂	419	酰胺键
3avm	SRKIDNLD	8	8	HIV整合酶重组抑制剂	402	酰胺键
3avn	SHKIDNLD	8	8	HIV整合酶重组抑制剂	394	酰胺键
3wne	PKIDNG	6	6	HIV整合酶天然配体	378	酰胺键
3wng	PKIDNp	6	6	HIV-1整合酶抑制剂	360	酰胺键
3wnh	PK[nle]DNv	6	6	HIV-1整合酶抑制剂	367	酰胺键
3zgc	GDEETGE	7	7	红细胞核因子配体	343	酰胺键
4k1e	GFCQRSIPPICFPD	14	14	胰蛋白酶抑制剂	605	酰胺键
4kel	GFCQRSIPPICFPN	14	14	胰蛋白酶抑制剂	609	酰胺键
4y1d	K[nle]DNv[45w]	6	6	HIV-1整合酶抑制剂	412	酰胺键
5n99	NQpWQ	5	5	链霉亲和素配体	371	酰胺键
5xn3	RGDINNNV	8	8	SPSB2-iNOS相互作用抑制剂	270	酰胺键
6jwm	RGDINNN	7	7	SPSB2-iNOS相互作用抑制剂	281	酰胺键
6jwn	RGDINNNVE	9	9	SPSB2-iNOS相互作用抑制剂	294	酰胺键
7k2e	GDEETGE	7	7	人源KEAP1蛋白抑制剂	360	酰胺键
7k2g	GDEEAGE	7	7	人源KEAP1蛋白抑制剂	403	酰胺键
7k2h	GDPETGE	7	7	人源KEAP1蛋白抑制剂	343	酰胺键
7k2m	GEPETGE	7	7	人源KEAP1蛋白抑制剂	320	酰胺键
6xbe	rrLcPVPE	8	8	NDM-1金属-β-内酰胺酶抑制剂	379	酰胺键
6xbf	rrLcPIPE	8	8	NDM-2金属-β-内酰胺酶抑制剂	452	酰胺键
1hqq	RCCHPQCGAVEEC	13	11	链霉亲和素配体	413	二硫键
1jbu	EEWEVLCWTWETCER	15	7	凝血因子Ⅶ抑制剂	908	二硫键
1smf	CTKSIPPEC	9	9	胰蛋白酶抑制剂	414	二硫键
1sle	CHPQGPPC	8	8	链霉亲和素配体	324	二硫键
1vpp	RGWVEICAADDYGRCLTE	18	9	生长素抑制剂	556	二硫键
1vwb	CHPQFC	6	6	链霉亲和素配体	306	二硫键
2ck0	CKEWLSTAPCG	11	10	血管紧张素Ⅱ抗体结合肽	504	二硫键
2nwn	CSWRGLENHRMC	12	12	丝氨酸蛋白酶抑制剂	597	二硫键
3g5v	CGADSYEMEEDGVRKC	16	16	EGFR肽段	603	二硫键
3p72	CTERMALHNLC	11	11	血小板糖蛋白1b抑制剂	521	二硫键
3wnf	CKIDNC	6	6	HIV-1整合酶抑制剂	432	二硫键
4ib5	GCRLYGFKIHGCG	13	11	CK2beta拮抗剂	456	二硫键
4m1d	CRIHIGPGRAFYTC	14	14	HIV-1 gp120蛋白V3域类似物	588	二硫键
4ou3	CNGRCG	6	5	猪氨肽酶N抑制剂	366	二硫键
5djc	DCAWHLGELVWCT	13	11	抗体结合肽	610	二硫键
5co5	GCCSHPACAGNNQHIC	16	15	芋螺毒素	692	二硫键
5eoc	CQLINTNGSWHIC	13	13	丙型肝炎病毒E2表位Ⅰ类似物	468	二硫键
5h5q	CRVDLQGWRRCRR	13	11	人源GPX4抑制剂	505	二硫键
5th2	CQFDQSTRRLKC	12	12	L5Q中间位变体类似物	709	二硫键
5vb9	CWVLEYDMFGALHCR	15	14	IL-17抗体抑制剂	571	二硫键
5wxr	GACSARGLENHAAC	14	12	尿激酶型纤溶酶原激活物抑制剂	526	二硫键
5xco	RRRRCPLYISYDPVCRRRR	19	11	K-Ras(G12D突变体)抑制剂	650	二硫键
6e5m	CTKSIPPQC	9	9	β-胰蛋白酶抑制剂	434	二硫键
1bm2	[slz][pY]VNVP	6	6	GBR2-sh2结构域高活性配体	336	其他环化
1bzh	DADE[flt]L[aea]	7	7	酪氨酸磷酸酶抑制剂	398	其他环化
1vwl	HPQGPPC([lea])K	9	8	链霉亲和素配体	300	其他环化
4zjx	C[dab]RWTKCL	8	7	肉毒杆菌神经毒素（血清型A）抑制剂	604	其他环化
5nes	cWwKkKkKwWc[8vh]	12	12	靶向铜绿假单胞菌糖蛋白的抗菌肽	259	其他环化
5ney	CwWkKkKkWwC[oxe]	12	12	靶向铜绿假单胞菌糖蛋白的抗菌肽	271	其他环化
5nf0	cWwKkKkKwWc[oxe]	12	12	靶向铜绿假单胞菌糖蛋白的抗菌肽	283	其他环化
6b67	M[pS]I[pY]VA[48v]	7	7	PPM1A活性调节剂	528	其他环化
6dn6	INNN[abu]	5	5	iNOS-SPSB蛋白-蛋白相互作用抑制剂	234	其他环化
6dn7	WDINNN[bal]	7	7	iNOS-SPSB蛋白-蛋白相互作用抑制剂	254	其他环化
6dn8	[gzj]VDINNN[cy3]	8	8	iNOS-SPSB蛋白-蛋白相互作用抑制剂	258	其他环化
6nnv	F[mea][9kk][sar]DV[mea]Y[sar]WYLCK	14	13	PD-L1抑制剂	510	其他环化
6u4a	WWIIP[aly]VK[aly]GC	11	11	BRD2-BD1抑制剂	587	其他环化
6u74	WKTI[aly]G[aly]TWRT[aly]QC	14	14	BRD2-BD1抑制剂	582	其他环化
6u8m	W[aly]KAILPG[aly]ILKTLHIC	17	17	BRD2-BD1抑制剂	504	其他环化
6wgn	GyFVNFRNFRTFRCG	15	14	K-Ras(G12D突变体)抑制剂	641	其他环化
6xci	cP[lwi][hyp]Epk[nle]	8	8	NDM-3金属-β-内酰胺酶抑制剂	457	其他环化
6xib	[b74]CKG[ftr][ftr]DHY[3wx]CA	12	11	PCSK9抑制剂	546	其他环化
6xic	[b74]CKa[ftr][ftr]DHY[3wx][dhl]	11	11	PCSK9抑制剂	518	其他环化
6xid	[v7m]CKa[ftr][ftr]PTY[3wx]CA	12	11	PCSK9抑制剂	537	其他环化
6xie	[b74]CAa[apd][ftr]QT[0a1][3wx]C	11	11	PCSK9抑制剂	496	其他环化
6xif	[v7s]GAa[apd][v7p][gnc][olt][0a1][3wx]G	11	11	PCSK9抑制剂	528	其他环化
6xs5	[48v]yIIDTPLGVFLSSLKR	17	17	人源Vps29抑制剂，结构稳定剂	529	其他环化
6xs7	[48v]yTTIYWTPLGTFPRIR	17	17	人源Vps30抑制剂，结构稳定剂	654	其他环化
6xs8	[48v]yGYDPLGLKYFA	13	13	人源Vps31抑制剂，结构稳定剂	380	其他环化
6xsa	[48v]YLPTITGVGHLWHPL	15	15	人源Vps32抑制剂，结构稳定剂	623	其他环化
6yw1	[48v]yVWLTDTWVLSRT	14	14	促进HIF脯氨酰羟化酶2结晶的环肽配体	671	其他环化
7bph	yFESVYAIWGTLCG	14	13	GNAS抑制剂	520	其他环化
7k2k	[bal]DEETGE	7	7	人源KEAP1蛋白抑制剂	349	其他环化
7k2l	[bal]NPETGE	7	7	人源KEAP1蛋白抑制剂	330	其他环化
7k2o	[abu]DPETGE	7	7	人源KEAP1蛋白抑制剂	346	其他环化
7k2p	[dav]DPETGE	7	7	人源KEAP1蛋白抑制剂	344	其他环化
7k2r	[b3a]DPETGE	7	7	人源KEAP1蛋白抑制剂	350	其他环化
7rov	A[060]PLYISYDPVCRA	14	12	K-Ras(G12D突变体)抑制剂	564	其他环化

PDB编号	环肽配体序列	肽链长度	环的大小	环肽功能	靶蛋白界面埋藏面积/Å²	环化类型
1e4w	SHFNEYE	8	8	TGF-α抗原表位类似物，与tAb2抗体结合	381	酰胺键
1sfi	GRCTKSIPPICFPD	14	14	胰蛋白酶抑制剂	612	酰胺键
2axi	PFE[6cw]LDWEFp	10	10	P53-HDM2配体	510	酰胺键
3av9	SAKIDNLD	8	8	HIV整合酶重组抑制剂	397	酰胺键
3ava	ALKIDNLD	8	8	HIV整合酶重组抑制剂	395	酰胺键
3avb	SLKIDNLD	8	8	HIV整合酶重组抑制剂	401	酰胺键
3avf	DLKIDNLD	8	8	HIV整合酶重组抑制剂	418	酰胺键
3avg	ADKIDNLD	8	8	HIV整合酶重组抑制剂	385	酰胺键
3avh	ARKIDNLD	8	8	HIV整合酶重组抑制剂	388	酰胺键
3avi	SLKIDNMD	8	8	HIV整合酶重组抑制剂	432	酰胺键
3avj	ALKIDNMD	8	8	HIV整合酶重组抑制剂	437	酰胺键
3avk	SLKIDNED	8	8	HIV整合酶重组抑制剂	419	酰胺键
3avm	SRKIDNLD	8	8	HIV整合酶重组抑制剂	402	酰胺键
3avn	SHKIDNLD	8	8	HIV整合酶重组抑制剂	394	酰胺键
3wne	PKIDNG	6	6	HIV整合酶天然配体	378	酰胺键
3wng	PKIDNp	6	6	HIV-1整合酶抑制剂	360	酰胺键
3wnh	PK[nle]DNv	6	6	HIV-1整合酶抑制剂	367	酰胺键
3zgc	GDEETGE	7	7	红细胞核因子配体	343	酰胺键
4k1e	GFCQRSIPPICFPD	14	14	胰蛋白酶抑制剂	605	酰胺键
4kel	GFCQRSIPPICFPN	14	14	胰蛋白酶抑制剂	609	酰胺键
4y1d	K[nle]DNv[45w]	6	6	HIV-1整合酶抑制剂	412	酰胺键
5n99	NQpWQ	5	5	链霉亲和素配体	371	酰胺键
5xn3	RGDINNNV	8	8	SPSB2-iNOS相互作用抑制剂	270	酰胺键
6jwm	RGDINNN	7	7	SPSB2-iNOS相互作用抑制剂	281	酰胺键
6jwn	RGDINNNVE	9	9	SPSB2-iNOS相互作用抑制剂	294	酰胺键
7k2e	GDEETGE	7	7	人源KEAP1蛋白抑制剂	360	酰胺键
7k2g	GDEEAGE	7	7	人源KEAP1蛋白抑制剂	403	酰胺键
7k2h	GDPETGE	7	7	人源KEAP1蛋白抑制剂	343	酰胺键
7k2m	GEPETGE	7	7	人源KEAP1蛋白抑制剂	320	酰胺键
6xbe	rrLcPVPE	8	8	NDM-1金属-β-内酰胺酶抑制剂	379	酰胺键
6xbf	rrLcPIPE	8	8	NDM-2金属-β-内酰胺酶抑制剂	452	酰胺键
1hqq	RCCHPQCGAVEEC	13	11	链霉亲和素配体	413	二硫键
1jbu	EEWEVLCWTWETCER	15	7	凝血因子Ⅶ抑制剂	908	二硫键
1smf	CTKSIPPEC	9	9	胰蛋白酶抑制剂	414	二硫键
1sle	CHPQGPPC	8	8	链霉亲和素配体	324	二硫键
1vpp	RGWVEICAADDYGRCLTE	18	9	生长素抑制剂	556	二硫键
1vwb	CHPQFC	6	6	链霉亲和素配体	306	二硫键
2ck0	CKEWLSTAPCG	11	10	血管紧张素Ⅱ抗体结合肽	504	二硫键
2nwn	CSWRGLENHRMC	12	12	丝氨酸蛋白酶抑制剂	597	二硫键
3g5v	CGADSYEMEEDGVRKC	16	16	EGFR肽段	603	二硫键
3p72	CTERMALHNLC	11	11	血小板糖蛋白1b抑制剂	521	二硫键
3wnf	CKIDNC	6	6	HIV-1整合酶抑制剂	432	二硫键
4ib5	GCRLYGFKIHGCG	13	11	CK2beta拮抗剂	456	二硫键
4m1d	CRIHIGPGRAFYTC	14	14	HIV-1 gp120蛋白V3域类似物	588	二硫键
4ou3	CNGRCG	6	5	猪氨肽酶N抑制剂	366	二硫键
5djc	DCAWHLGELVWCT	13	11	抗体结合肽	610	二硫键
5co5	GCCSHPACAGNNQHIC	16	15	芋螺毒素	692	二硫键
5eoc	CQLINTNGSWHIC	13	13	丙型肝炎病毒E2表位Ⅰ类似物	468	二硫键
5h5q	CRVDLQGWRRCRR	13	11	人源GPX4抑制剂	505	二硫键
5th2	CQFDQSTRRLKC	12	12	L5Q中间位变体类似物	709	二硫键
5vb9	CWVLEYDMFGALHCR	15	14	IL-17抗体抑制剂	571	二硫键
5wxr	GACSARGLENHAAC	14	12	尿激酶型纤溶酶原激活物抑制剂	526	二硫键
5xco	RRRRCPLYISYDPVCRRRR	19	11	K-Ras(G12D突变体)抑制剂	650	二硫键
6e5m	CTKSIPPQC	9	9	β-胰蛋白酶抑制剂	434	二硫键
1bm2	[slz][pY]VNVP	6	6	GBR2-sh2结构域高活性配体	336	其他环化
1bzh	DADE[flt]L[aea]	7	7	酪氨酸磷酸酶抑制剂	398	其他环化
1vwl	HPQGPPC([lea])K	9	8	链霉亲和素配体	300	其他环化
4zjx	C[dab]RWTKCL	8	7	肉毒杆菌神经毒素（血清型A）抑制剂	604	其他环化
5nes	cWwKkKkKwWc[8vh]	12	12	靶向铜绿假单胞菌糖蛋白的抗菌肽	259	其他环化
5ney	CwWkKkKkWwC[oxe]	12	12	靶向铜绿假单胞菌糖蛋白的抗菌肽	271	其他环化
5nf0	cWwKkKkKwWc[oxe]	12	12	靶向铜绿假单胞菌糖蛋白的抗菌肽	283	其他环化
6b67	M[pS]I[pY]VA[48v]	7	7	PPM1A活性调节剂	528	其他环化
6dn6	INNN[abu]	5	5	iNOS-SPSB蛋白-蛋白相互作用抑制剂	234	其他环化
6dn7	WDINNN[bal]	7	7	iNOS-SPSB蛋白-蛋白相互作用抑制剂	254	其他环化
6dn8	[gzj]VDINNN[cy3]	8	8	iNOS-SPSB蛋白-蛋白相互作用抑制剂	258	其他环化
6nnv	F[mea][9kk][sar]DV[mea]Y[sar]WYLCK	14	13	PD-L1抑制剂	510	其他环化
6u4a	WWIIP[aly]VK[aly]GC	11	11	BRD2-BD1抑制剂	587	其他环化
6u74	WKTI[aly]G[aly]TWRT[aly]QC	14	14	BRD2-BD1抑制剂	582	其他环化
6u8m	W[aly]KAILPG[aly]ILKTLHIC	17	17	BRD2-BD1抑制剂	504	其他环化
6wgn	GyFVNFRNFRTFRCG	15	14	K-Ras(G12D突变体)抑制剂	641	其他环化
6xci	cP[lwi][hyp]Epk[nle]	8	8	NDM-3金属-β-内酰胺酶抑制剂	457	其他环化
6xib	[b74]CKG[ftr][ftr]DHY[3wx]CA	12	11	PCSK9抑制剂	546	其他环化
6xic	[b74]CKa[ftr][ftr]DHY[3wx][dhl]	11	11	PCSK9抑制剂	518	其他环化
6xid	[v7m]CKa[ftr][ftr]PTY[3wx]CA	12	11	PCSK9抑制剂	537	其他环化
6xie	[b74]CAa[apd][ftr]QT[0a1][3wx]C	11	11	PCSK9抑制剂	496	其他环化
6xif	[v7s]GAa[apd][v7p][gnc][olt][0a1][3wx]G	11	11	PCSK9抑制剂	528	其他环化
6xs5	[48v]yIIDTPLGVFLSSLKR	17	17	人源Vps29抑制剂，结构稳定剂	529	其他环化
6xs7	[48v]yTTIYWTPLGTFPRIR	17	17	人源Vps30抑制剂，结构稳定剂	654	其他环化
6xs8	[48v]yGYDPLGLKYFA	13	13	人源Vps31抑制剂，结构稳定剂	380	其他环化
6xsa	[48v]YLPTITGVGHLWHPL	15	15	人源Vps32抑制剂，结构稳定剂	623	其他环化
6yw1	[48v]yVWLTDTWVLSRT	14	14	促进HIF脯氨酰羟化酶2结晶的环肽配体	671	其他环化
7bph	yFESVYAIWGTLCG	14	13	GNAS抑制剂	520	其他环化
7k2k	[bal]DEETGE	7	7	人源KEAP1蛋白抑制剂	349	其他环化
7k2l	[bal]NPETGE	7	7	人源KEAP1蛋白抑制剂	330	其他环化
7k2o	[abu]DPETGE	7	7	人源KEAP1蛋白抑制剂	346	其他环化
7k2p	[dav]DPETGE	7	7	人源KEAP1蛋白抑制剂	344	其他环化
7k2r	[b3a]DPETGE	7	7	人源KEAP1蛋白抑制剂	350	其他环化
7rov	A[060]PLYISYDPVCRA	14	12	K-Ras(G12D突变体)抑制剂	564	其他环化

类型	代表算法	算法简介	算法目的
基于对接的虚拟筛选算法	AutoDock CrankPep^[93]， HADDOCK^[94]等分子对接算法	将环肽结构库中的分子与靶标蛋白对接，基于对接打分富集可能结合靶标的环肽。对接打分是对环肽和靶标蛋白结合的粗略但高效的评估	从现有环肽、已知结构环肽或某一类环肽等环肽库中富集可能结合靶标蛋白的分子，为实验发现未知的结合环肽提供候选分子
借助分子动力学模拟的设计算法	REMD^[69]，META^[72]， BE-META^[73]等增强采样算法	借助于分子动力学模拟增强采样算法对环肽以及环肽与靶标蛋白的复合物结构进行采样。通过动力学采样对目标环肽和靶标蛋白的结合能进行精细的计算和比较	对已知结合的环肽分子进行分析和改造设计，估算结合自由能，研究各残基对结合的贡献，找到对环肽进行改进的可能方案
从头设计算法	Rosetta Anchor Extension^[34]	以某个对结合能贡献较大的基团为起点，在靶标蛋白表面通过主链优化采样与序列设计生长出全新的环肽	不受限于已知结合环肽或是环肽结构库，针对靶标蛋白从头设计环肽配体，并能引入化学修饰与非天然氨基酸
具有跨膜活性的环肽分子设计	Rosetta^[56]	引入主链酰胺键的N-甲基化修饰或降低侧链极性的非天然氨基酸	在设计中加入环肽跨膜活性的考量

基于靶标结构的环肽分子计算设计

Target structure based computational design of cyclic peptides

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算法名称	目标任务	测试体系或数据集	测试集规模	环肽序列长度	算法性能
MODPEP 2.0^[50]	仅SS-环肽结构建模	非冗余SSCP库	193	约30	前100构象与前10构象的平均C_α RMSD为2.20 Å和1.66 Å，优于mETKDG与PEP-FOLD
Peplook^[87]	环肽结构建模	环肽建模困难数据集	38	5～30	平均BB-RMSD为3.8 Å,优于PEP-FOLD
PEPstrMOD^[77]	环肽结构建模	CyclicPep	34	10～30	平均C_α-RMSD为4.06 Å,优于PEP-FOLD
PEP-FOLD^{[80, 82-83]}	环肽结构建模	环肽建模困难数据集	34	10～30	平均RMS为2.75 Å
I-TASSER^[76]	环肽结构建模	环肽建模困难数据集	35	10～30	平均BB-RMSD为2.5 Å
mETKDG^[52]	环肽结构构象生成	mc-PEP-set	2	10，11	最优BB-RMSD分布均值分别为0.60 Å，1.27 Å
AutoDock CrankPep^[96]	环肽配体对接	PDB数据库中非冗余环肽-蛋白复合物	CNCP: 18; SSCP: 20	CNCP: 6～14; SSCP: 6～20	对于CNCP,SSCP的最优平均fnc分别为0.86和0.70
HADDOCK 2.4^[94]	环肽配体对接	PDB数据库中非冗余环肽-蛋白复合物	CNCP: 18; SSCP: 12	CNCP: 6～14; SSCP: 6～14	CNCP的平均RMSD为1.5～2.0 Å（略优于AutoDock CrankPep）,SSCP的最优平均RMSD为3.0 Å
DES3PI^[105]	环肽配体从头设计	靶标蛋白：Ras， Mcl-1，Aβ protofibril	—	—	生成环肽配体的AutoDock CrankPep对接打分可以达到-9～-12 kcal/mol
Rosetta	环肽单体理性从头设计^[55]	—	—	7～14	生成了200种环肽结构，其中部分进行了结构解析，BB-RMSD<1.6 Å
	环肽配体从头设计^[34]	靶标蛋白：HDAC2，HDAC6	—	7～10	设计环肽配体实验测得最优IC₅₀为：HDAC2 9.1 nmol/L；HDAC6 5.4 nmol/L
	跨膜活性环肽从头设计^[56]	—	—	6～12	生成了具有跨膜活性的环肽结构，与实验解析结构的BB-RMSD<1.5 Å，具有跨膜活性与较好的口服利用率

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