Honglin Li

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Name: 李洪林; Li, HongLin

Organization: Chinese Academy of Sciences , China

Department: Shanghai Institute of Materia Medica

Title: Professor(PhD)

Chemicals
References

Novel Drugs Targeting the Epigenome

Co-reporter:Zhuo Chen

Current Pharmacology Reports 2017 Volume 3( Issue 5) pp:268-285

Publication Date(Web):15 August 2017

DOI:10.1007/s40495-017-0100-7

Epigenetic drug discovery has its beginning in the cancer research arena, focusing first on DNA methylation and histone deacetylation. There are currently two DNA methyltransferase (DNMT) inhibitors and four histone deacetylase (HDAC) inhibitors approved by the US Food and Drug Administration (FDA) during the past 13 years. Over the past few years, breakthrough discoveries of chromatin-modifying enzymes and associated mechanisms have exploded, providing new insights into the role of epigenetic control in gene regulation and leading to the discovery of a variety of new and specific drug targets. Among them, epigenetic “reader”—bromodomain and extra-terminal protein (BET), “writers”—disruptor of telomeric silencing 1-like (DOT1L), enhancer of zeste homolog 2 (EZH2), and protein arginine methyltransferase 5 (PRMT5), and “erasers”—lysine-specific histone demethylase 1 (LSD1) as well as isocitrate dehydrogenase (IDH) attract greater attention due to the ongoing clinical trials. This article provides a brief overview of new drugs modulating the above epigenetic targets, including their indication, mechanism of action, and disclosed chemical structures. The trend of epigenetic drug approval in the following few years is expectable, at least partially, from current clinical trials summarized in this review.

Structural analysis of recombinant human ubiquitin-conjugating enzyme UbcH5c

Co-reporter:Fangshu Wu, Junsheng Zhu, Honglin Li, Lili Zhu

Acta Pharmaceutica Sinica B 2017 Volume 7, Issue 3(Issue 3) pp:

Publication Date(Web):1 May 2017

DOI:10.1016/j.apsb.2016.12.008

UbcH5c belongs to the ubiquitin-conjugating enzyme family and plays an important role in catalyzing ubiquitination during TNF-α--triggered NF-κB activation. Therefore, UbcH5c is a potent therapeutic target for the treatment of inflammatory and autoimmune diseases induced by aberrant activation of NF-κB. In this study, we established a stable expression system for recombinant UbcH5c and solved the crystal structure of UbcH5c belonging to space group P22121 with one molecule in the asymmetric unit. This study provides the basis for further study of UbcH5c including the design of UbcH5c inhibitors.A stable expression system for recombinant UbcH5c was established and one crystal structure of UbcH5c solved at a high resolution. This study provides the basis for further study of UbcH5c including the design of UbcH5c inhibitors.Download high-res image (317KB)Download full-size image

Discovery and Structural Optimization of N5-Substituted 6,7-Dioxo-6,7-dihydropteridines as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation

Co-reporter:Yongjia Hao, Xia Wang, Tao Zhang, Deheng Sun, Yi Tong, Yuqiong Xu, Haiyang Chen, Linjiang Tong, Lili Zhu, Zhenjiang Zhao, Zhuo Chen, Jian Ding, Hua Xie, Yufang Xu, and Honglin Li

Journal of Medicinal Chemistry 2016 Volume 59(Issue 15) pp:7111-7124

Publication Date(Web):July 11, 2016

DOI:10.1021/acs.jmedchem.6b00403

EGFR-targeted inhibitors (gefitinib and erlotinib) provided an effective strategy for the treatment of non-small-cell lung cancer. However, the EGFR T790M secondary mutation has become a leading cause of clinically acquired resistance to these agents. Herein, on the basis of the previously reported irreversible EGFR inhibitor (compound 9), we present a structure-based design approach, which is rationalized via analyzing its binding model and comparing the differences of gatekeeper pocket between the T790M mutant and wild-type (WT) EGFR kinases. Guided by these results, a novel 6,7-dioxo-6,7-dihydropteridine scaffold was discovered and hydrophobic modifications at N5-position were conducted to strengthen nonpolar contacts and improve mutant selectivity over EGFRWT. Finally, the most representative compound 17d was identified. This work demonstrates the power of structure-based strategy in discovering lead compounds and provides molecular insights into the selectivity of EGFRL858R/T790M over EGFRWT, which may play an important role in designing new classes of mutant-selective EGFR inhibitors.

Discovery and Rational Design of Natural-Product-Derived 2-Phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine Analogs as Novel and Potent Dipeptidyl Peptidase 4 (DPP-4) Inhibitors for the Treatment of Type 2 Diabetes

Co-reporter:Shiliang Li; Hongling Xu; Shichao Cui; Fangshu Wu; Youli Zhang; Mingbo Su; Yinghui Gong; Shaobing Qiu; Qian Jiao; Chun Qin; Jiwei Shan; Ming Zhang; Jiawei Wang; Qiao Yin; Minghao Xu; Xiaofeng Liu; Rui Wang; Lili Zhu; Jia Li; Yufang Xu; Hualiang Jiang; Zhenjiang Zhao; Jingya Li

Journal of Medicinal Chemistry 2016 Volume 59(Issue 14) pp:6772-6790

Publication Date(Web):July 9, 2016

DOI:10.1021/acs.jmedchem.6b00505

Starting from the lead isodaphnetin, a natural product inhibitor of DPP-4 discovered through a target fishing docking based approach, a series of novel 2-phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine derivatives as potent DPP-4 inhibitors are rationally designed utilizing highly efficient 3D molecular similarity based scaffold hopping as well as electrostatic complementary methods. Those ingenious drug design strategies bring us approximate 7400-fold boost in potency. Compounds 22a and 24a are the most potent ones (IC50 ≈ 2.0 nM) with good pharmacokinetic profiles. Compound 22a demonstrated stable pharmacological effect. A 3 mg/kg oral dose provided >80% inhibition of DPP-4 activity within 24 h, which is comparable to the performance of the long-acting control omarigliptin. Moreover, the efficacy of 22a in improving the glucose tolerance is also comparable with omarigliptin. In this study, not only promising DPP-4 inhibitors as long acting antidiabetic that are clinically on demand are identified, but the target fish docking and medicinal chemistry strategies were successfully implemented.

Discovery and Rational Design of Pteridin-7(8H)-one-Based Inhibitors Targeting FMS-like Tyrosine Kinase 3 (FLT3) and Its Mutants

Co-reporter:Deheng Sun; Yu Yang; Jiankun Lyu; Wei Zhou; Wenlin Song; Zhenjiang Zhao; Zhuo Chen; Yufang Xu

Journal of Medicinal Chemistry 2016 Volume 59(Issue 13) pp:6187-6200

Publication Date(Web):June 7, 2016

DOI:10.1021/acs.jmedchem.6b00374

FLT3 has been validated as a therapeutic target for the treatment of acute myeloid leukemia (AML). In this paper, we describe for the first time, pteridin-7(8H)-one as a scaffold for potent FLT3 inhibitors derived from structural optimizations on irreversible EGFR inhibitors. The representative inhibitor (31) demonstrates single-digit nanomolar inhibition against FLT3 and subnanomolar KD for drug-resistance FLT3 mutants. In profiling of the in vitro tumor cell lines, it shows good selectivity against AML cells harboring FLT3-ITD mutations over other leukemia and solid tumor cell lines. The mechanism of action study illustrates that pteridin-7(8H)-one derivatives suppress the phosphorylation of FLT3 and its downstream pathways, thereby inducing G0/G1 cell cycle arrest and apoptosis in AML cells. In in vivo studies, 31 significantly suppresses the tumor growth in MV4–11 xenograft model. Overall, we provide a structurally distinct chemical scaffold with which to develop FLT3 mutants-selective inhibitors for AML treatment.

Enhancing the Enrichment of Pharmacophore-Based Target Prediction for the Polypharmacological Profiles of Drugs

Co-reporter:Xia Wang; Chenxu Pan; Jiayu Gong; Xiaofeng Liu

Journal of Chemical Information and Modeling 2016 Volume 56(Issue 6) pp:1175-1183

Publication Date(Web):May 17, 2016

DOI:10.1021/acs.jcim.5b00690

PharmMapper is a web server for drug target identification by reversed pharmacophore matching the query compound against an annotated pharmacophore model database, which provides a computational polypharmacology prediction approach for drug repurposing and side effect risk evaluation. But due to the inherent nondiscriminative feature of the simple fit scores used for prediction results ranking, the signal/noise ratio of the prediction results is high, posing a challenge for predictive reliability. In this paper, we improved the predictive accuracy of PharmMapper by generating a ligand–target pairwise fit score matrix from profiling all the annotated pharmacophore models against corresponding ligands in the original complex structures that were used to extract these pharmacophore models. The matrix reflects the noise baseline of fit score distribution of the background database, thus enabling estimation of the probability of finding a given target randomly with the calculated ligand–pharmacophore fit score. Two retrospective tests were performed which confirmed that the probability-based ranking score outperformed the simple fit score in terms of identification of both known drug targets and adverse drug reaction related off-targets.

Structure-based design of potent human dihydroorotate dehydrogenase inhibitors as anticancer agents

Co-reporter:Wenlin Song, Shiliang Li, Yi Tong, Jiawei Wang, Lina Quan, Zhuo Chen, Zhenjiang Zhao, Yufang Xu, Lili Zhu, Xuhong Qian and Honglin Li

MedChemComm 2016 vol. 7(Issue 7) pp:1441-1448

Publication Date(Web):13 Jun 2016

DOI:10.1039/C6MD00179C

It has been proven that inhibiting human dihydroorotate dehydrogenase (hDHODH) restricts the growth of rapidly proliferating cells, thus hDHODH can be developed as a promising target for the treatment of immunological disease and cancer. Here, a succession of substituted hydrazino-thiazole derivatives were designed, synthesized, and biologically evaluated through structure-based optimization, of which compound 22 was the most potent inhibitor of hDHODH with an IC50 value of 1.8 nM. Furthermore, 22 exhibited much better antiproliferative activity than brequinar, both in HCT-116 and BxPC-3 cancer cell lines. Flow cytometry analysis revealed that 22 induced S phase cell cycle arrest and promoted induction of apoptosis. All results established a proof that blocking the pyrimidine de novo synthesis pathway by inhibiting the rate-limiting enzyme hDHODH is an attractive therapy for cancer.

Isoindole-1,3-dione derivatives as RSK2 inhibitors: synthesis, molecular docking simulation and SAR analysis

Co-reporter:Wei Zhou, Shiliang Li, Weiqiang Lu, Jun Yuan, Yufang Xu, Honglin Li, Jin Huang and Zhenjiang Zhao

MedChemComm 2016 vol. 7(Issue 2) pp:292-296

Publication Date(Web):25 Nov 2015

DOI:10.1039/C5MD00469A

RSK2 (p90 ribosomal S6 kinase 2) is a serine/threonine kinase expressed in a variety of cancers. Molecular-targeted inhibition of RSK2 as a potential therapeutic strategy for human cancers has been documented. In this work, a series of isoindole-1,3-dione derivatives as novel RSK2 inhibitors were designed and synthesized from a hit discovered in our previous study. Some compounds were confirmed to be moderately potent RSK2 inhibitors with IC50 values of about 0.5 μM. Structure–activity relationship analysis and binding mode studies by molecular docking were performed.

Biological evaluation of quinoline derivatives as inhibitors of human dihydroorotate dehydrogenase

Co-reporter:Jiawei Wang, Yanyan Diao, Junsheng Zhu, Shiliang Li, Zhenjiang Zhao, Honglin Li and Lili Zhu

MedChemComm 2016 vol. 7(Issue 5) pp:853-858

Publication Date(Web):05 Feb 2016

DOI:10.1039/C6MD00024J

Human dihydroorotate dehydrogenase (hDHODH) is an enzyme that catalyzes the fourth step in de novo pyrimidine biosynthesis, and its inhibitors restrict the growth of rapidly proliferating cells. Therefore, hDHODH has been reported as an attractive target for the treatment of cancer and autoimmune diseases. In this study, several quinoline derivatives were identified as potent inhibitors against hDHODH, among which compound A9 was the most potent one with an IC50 value of 9.7 nM. We further verified by thermal shift assay (TSA), surface plasmon resonance (SPR) and X-ray crystallography that A9 could directly bind to the target hDHODH. The crystal structure of hDHODH in complex with compound A9 was refined to 1.90 Å and the binding mode of compound A9 was summarized. Moreover, structure–activity relationship (SAR) analysis of quinoline derivatives with hDHODH indicated that quinoline derivatives with a carboxyl group in R1, a bromine atom in R2 and a para-alkyl-substituted phenyl group in R5, were beneficial for potency against hDHODH, which plays an important role in inhibitor design and optimization.

Design, Synthesis, X-ray Crystallographic Analysis, and Biological Evaluation of Thiazole Derivatives as Potent and Selective Inhibitors of Human Dihydroorotate Dehydrogenase

Co-reporter:Junsheng Zhu; Le Han; Yanyan Diao; Xiaoli Ren; Minghao Xu; Liuxin Xu; Shiliang Li; Qiang Li; Dong Dong; Jin Huang; Xiaofeng Liu; Zhenjiang Zhao; Rui Wang; Lili Zhu; Yufang Xu; Xuhong Qian

Journal of Medicinal Chemistry 2015 Volume 58(Issue 3) pp:1123-1139

Publication Date(Web):January 12, 2015

DOI:10.1021/jm501127s

Human dihydroorotate dehydrogenase (HsDHODH) is a flavin-dependent mitochondrial enzyme that has been certified as a potential therapeutic target for the treatment of rheumatoid arthritis and other autoimmune diseases. On the basis of lead compound 4, which was previously identified as potential HsDHODH inhibitor, a novel series of thiazole derivatives were designed and synthesized. The X-ray complex structures of the promising analogues 12 and 33 confirmed that these inhibitors bind at the putative ubiquinone binding tunnel and guided us to explore more potent inhibitors, such as compounds 44, 46, and 47 which showed double digit nanomolar activities of 26, 18, and 29 nM, respectively. Moreover, 44 presented considerable anti-inflammation effect in vivo and significantly alleviated foot swelling in a dose-dependent manner, which disclosed that thiazole-scaffold analogues can be developed into the drug candidates for the treatment of rheumatoid arthritis by suppressing the bioactivity of HsDHODH.

An Accurate Metalloprotein-Specific Scoring Function and Molecular Docking Program Devised by a Dynamic Sampling and Iteration Optimization Strategy

Co-reporter:Fang Bai, Sha Liao, Junfeng Gu, Hualiang Jiang, Xicheng Wang, and Honglin Li

Journal of Chemical Information and Modeling 2015 Volume 55(Issue 4) pp:833-847

Publication Date(Web):March 6, 2015

DOI:10.1021/ci500647f

Metalloproteins, particularly zinc metalloproteins, are promising therapeutic targets, and recent efforts have focused on the identification of potent and selective inhibitors of these proteins. However, the ability of current drug discovery and design technologies, such as molecular docking and molecular dynamics simulations, to probe metal–ligand interactions remains limited because of their complicated coordination geometries and rough treatment in current force fields. Herein we introduce a robust, multiobjective optimization algorithm-driven metalloprotein-specific docking program named MpSDock, which runs on a scheme similar to consensus scoring consisting of a force-field-based scoring function and a knowledge-based scoring function. For this purpose, in this study, an effective knowledge-based zinc metalloprotein-specific scoring function based on the inverse Boltzmann law was designed and optimized using a dynamic sampling and iteration optimization strategy. This optimization strategy can dynamically sample and regenerate decoy poses used in each iteration step of refining the scoring function, thus dramatically improving both the effectiveness of the exploration of the binding conformational space and the sensitivity of the ranking of the native binding poses. To validate the zinc metalloprotein-specific scoring function and its special built-in docking program, denoted MpSDockZn, an extensive comparison was performed against six universal, popular docking programs: Glide XP mode, Glide SP mode, Gold, AutoDock, AutoDock4Zn, and EADock DSS. The zinc metalloprotein-specific knowledge-based scoring function exhibited prominent performance in accurately describing the geometries and interactions of the coordination bonds between the zinc ions and chelating agents of the ligands. In addition, MpSDockZn had a competitive ability to sample and identify native binding poses with a higher success rate than the other six docking programs.

Identification of diverse natural products as falcipain-2 inhibitors through structure-based virtual screening

Co-reporter:Liyan Wang, Shoude Zhang, Junsheng Zhu, Lili Zhu, Xiaofeng Liu, Lei Shan, Jin Huang, Weidong Zhang, Honglin Li

Bioorganic & Medicinal Chemistry Letters 2014 Volume 24(Issue 5) pp:1261-1264

Publication Date(Web):1 March 2014

DOI:10.1016/j.bmcl.2014.01.074

Ten natural compounds are successfully identified as falcipain-2 (FP-2) inhibitors from our in-house natural products database using structure-based virtual screening, which show moderate inhibitory activities against FP-2 with IC50 values ranging from 3.18 to 68.19 μM. While one of the inhibitors (compound 5) also exhibits in vitro antiplasmodial activity against chloroquine sensitive strain (3D7) and chloroquine resistant strain (Dd2) of Plasmodium falciparum in the micromolar range (IC50s = 5.54 μM and 4.05 μM against 3D7 cells and Dd2 cells, respectively). Furthermore, the predicted binding poses are analyzed to explain the structure–activity relationships, which will be helpful for further structural modifications.

Discovery of Pteridin-7(8H)-one-Based Irreversible Inhibitors Targeting the Epidermal Growth Factor Receptor (EGFR) Kinase T790M/L858R Mutant

Co-reporter:Wei Zhou ; Xiaofeng Liu ; Zhengchao Tu ; Lianwen Zhang ; Xin Ku ; Fang Bai ; Zhenjiang Zhao ; Yufang Xu ; Ke Ding

Journal of Medicinal Chemistry 2013 Volume 56(Issue 20) pp:7821-7837

Publication Date(Web):September 22, 2013

DOI:10.1021/jm401045n

The EGFR T790M variant is an important mutation, resulting in approximately 50% of the clinically acquired resistance to approved EGFR inhibitors. Starting with a previously reported pyrimidine-based EGFR inhibitor, a novel pteridin-7(8H)-one scaffold with a high 3D similarity was found and transformed into irreversible inhibitors of the EGFR T790M mutant. The most potent compounds, 3q and 3x, exhibited excellent enzyme inhibitory activities, with subnanomolar IC50 values for both the wild-type and T790M/L858R double mutant EGFRs, as well as potent cellular antiproliferative activities against both gefitinib-sensitive and -resistant cancer cell lines. The in vivo antitumor efficacy study demonstrated that compound 3x significantly inhibited tumor growth and induced tumor stasis in an EGFR-T790M/L858R-driven human nonsmall-cell lung cancer xenograft mouse model. This work demonstrated the utility of this sophisticated computational design strategy for fast 3D scaffold hopping with competitive bioactivities to meet an important clinical need.

Novel Selective and Potent Inhibitors of Malaria Parasite Dihydroorotate Dehydrogenase: Discovery and Optimization of Dihydrothiophenone Derivatives

Co-reporter:Minghao Xu ; Junsheng Zhu ; Yanyan Diao ; Hongchang Zhou ; Xiaoli Ren ; Deheng Sun ; Jin Huang ; Dongmei Han ; Zhenjiang Zhao ; Lili Zhu ; Yufang Xu

Journal of Medicinal Chemistry 2013 Volume 56(Issue 20) pp:7911-7924

Publication Date(Web):September 27, 2013

DOI:10.1021/jm400938g

Taking the emergence of drug resistance and lack of effective antimalarial vaccines into consideration, it is of significant importance to develop novel antimalarial agents for the treatment of malaria. Herein, we elucidated the discovery and structure–activity relationships of a series of dihydrothiophenone derivatives as novel specific inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH). The most promising compound, 50, selectively inhibited PfDHODH (IC50 = 6 nM, with >14 000-fold species-selectivity over hDHODH) and parasite growth in vitro (IC50 = 15 and 18 nM against 3D7 and Dd2 cells, respectively). Moreover, an oral bioavailability of 40% for compound 50 was determined from in vivo pharmacokinetic studies. These results further indicate that PfDHODH is an effective target for antimalarial chemotherapy, and the novel scaffolds reported in this work might lead to the discovery of new antimalarial agents.

Jatropholane-Type Diterpenes from Euphorbia sikkimensis

Co-reporter:Da-Song Yang ; You-Li Zhang ; Wei-Bing Peng ; Li-Yan Wang ; Zi-Lei Li ; Xue Wang ; Ke-Chun Liu ; Yong-Ping Yang ; Hong-Lin Li ;Xiao-Li Li

Journal of Natural Products 2013 Volume 76(Issue 2) pp:265-269

Publication Date(Web):January 17, 2013

DOI:10.1021/np300799n

Four new jatropholane-type diterpenes (1–4), named sikkimenoids A–D, were isolated from the aerial parts of Euphorbia sikkimensis. The structural elucidations of 1–4 were accomplished by extensive NMR analyses, and their absolute configurations were established by ECD calculations. Compound 2 exhibited weak antiangiogenic activity with an IC50 value of 43.0 μM when evaluated using a zebrafish model.

SimG: An Alignment Based Method for Evaluating the Similarity of Small Molecules and Binding Sites

Co-reporter:Chaoqian Cai, Jiayu Gong, Xiaofeng Liu, Daqi Gao, and Honglin Li

Journal of Chemical Information and Modeling 2013 Volume 53(Issue 8) pp:2103-2115

Publication Date(Web):July 28, 2013

DOI:10.1021/ci400139j

In this study, a Gaussian volume overlap and chemical feature based molecular similarity metric was devised, and a downhill simplex searching was carried out to evaluate the corresponding similarity. By representing the shapes of both the candidate small molecules and the binding site with chemical features and comparing the corresponding Gaussian volumes overlaps, the active compounds could be identified. These two aspects compose the proposed method named SimG which supports both structure-based and ligand-based strategies. The validity of the proposed method was examined by analyzing the similarity score variation between actives and decoys as well as correlation among distinct reference methods. A retrospective virtual screening test was carried out on DUD data sets, demonstrating that the performance of structure-based shape matching virtual screening in DUD data sets is substantially dependent on some physical properties, especially the solvent-exposure extent of the binding site: The enrichments of targets with less solvent-exposed binding sites generally exceeds that of the one with more solvent-exposed binding sites and even surpasses the corresponding ligand-based virtual screening.

Substituted indolin-2-ones as p90 ribosomal S6 protein kinase 2 (RSK2) inhibitors: Molecular docking simulation and structure–activity relationship analysis

Co-reporter:Ye Zhong, Mengzhu Xue, Xue Zhao, Jun Yuan, Xiaofeng Liu, Jin Huang, Zhenjiang Zhao, Honglin Li, Yufang Xu

Bioorganic & Medicinal Chemistry 2013 Volume 21(Issue 7) pp:1724-1734

Publication Date(Web):1 April 2013

DOI:10.1016/j.bmc.2013.01.047

Discovery of new potent inhibitors for carbonic anhydrase IX by structure-based virtual screening

Co-reporter:Liyan Wang, Chunmei Yang, Weiqiang Lu, Li Liu, Rui Gao, Sha Liao, Zhenjiang Zhao, Lili Zhu, Yufang Xu, Honglin Li, Jin Huang, Weiping Zhu

Bioorganic & Medicinal Chemistry Letters 2013 Volume 23(Issue 12) pp:3496-3499

Publication Date(Web):15 June 2013

DOI:10.1016/j.bmcl.2013.04.048

Through structure-based virtual screening, some dozen of benzene sulfonamides with novel scaffolds are identified as potent inhibitors against carbonic anhydrase (CA) IX with IC50 values ranging from 2.86 to 588.34 nM. Among them, compounds 1 and 9 show high selectivity against tumor-target CA IX over CA II (the selectivity ratios are 21.3 and 136.6, respectively). The possible binding poses of hit compounds are also explored and the selectivity is elucidated by molecular docking simulations. The hit compounds discovered in this work would provide novel scaffolds for further hit-to-lead optimization.

Discovery of non-peptide inhibitors of Plasmepsin II by structure-based virtual screening

Co-reporter:Yuwei Song, Huangtao Jin, Xiaofeng Liu, Lili Zhu, Jin Huang, Honglin Li

Bioorganic & Medicinal Chemistry Letters 2013 Volume 23(Issue 7) pp:2078-2082

Publication Date(Web):1 April 2013

DOI:10.1016/j.bmcl.2013.01.128

Plasmepsin II (PM II) is an attractive target for anti-malaria drug discovery, which involves in host hemoglobin degradation in the acidic food vacuole. In this study, we demonstrated the successful use of structure-based virtual screening to identify inhibitors of PM II from two chemical database. Five novel non-peptide inhibitors were identified and revealed moderate inhibitory potencies with IC50 ranged from 4.62 ± 0.39 to 9.47 ± 0.71 μM. The detailed analysis of binding modes using docking simulations for five inhibitors showed that the inhibitors could be stabilized by forming multiple hydrogen bonds with catalytic residues (Asp 34 and Asp 214) and also with other key residues.

Triazole and Benzotriazole Derivatives as Novel Inhibitors for p90 Ribosomal S6 Protein Kinase 2: Synthesis, Molecular Docking and SAR Analysis

Co-reporter:Jun Yuan;Ye Zhong;Shiliang Li;Xue Zhao;Guoqin Luan;Zhenjiang Zhao;Jin Huang;Yufang Xu

Chinese Journal of Chemistry 2013 Volume 31( Issue 9) pp:1192-1198

Publication Date(Web):

DOI:10.1002/cjoc.201300443

Abstract

A series of triazole and benzotriazole derivatives as novel p90 ribosomal S6 protein kinase 2 (RSK2) inhibitors were designed and synthesized. The in vitro activities against RSK2 were evaluated, and among 14 compounds, compounds 5, 6, 11, 12, 13 and 14 exhibited enzyme IC₅₀ values of 8.91, 2.86, 3.19, 3.05, 4.49 and 2.09 µmol/L respectively. The proposed binding modes were simulated using molecular docking method, and the docking results coupled with the structure-activity relationship (SAR) analysis indicated that all these active compounds bound to the RSK2 ATP binding site at NTKD, and the electron-donating groups on the 4-position of phenyl were the determinant point for the inhibitory activity.

Co-reporter:Chaoqian Cai;Jiayu Gong;Xiaofeng Liu;Daqi Gao

Chinese Journal of Chemistry 2013 Volume 31( Issue 9) pp:1123-1132

Publication Date(Web):

DOI:10.1002/cjoc.201300390

Abstract

Molecular similarity has long been a hot topic, which has been evaluated and compared by various approaches and plays a significant role in protein-ligand and protein-protein interactions recognition. There are currently many types of molecular similarity evaluation methods with their own advantages and disadvantages. Molecular fingerprints are the most common methods for molecular similarity evaluation which only concern about rapid 2D common substructure retrieval but lack the ability to encode the information about 3D conformers. 3D molecular descriptor based methods bear the advantages of representing the structure information of a conformer, but the descriptors are not guaranteed to describe the molecules precisely. Molecular alignment based methods try to superimpose two molecules and evaluate the similarity using the optimal poses which are generally more precise than the molecular descriptor but require a time-consuming optimization process. Pharmacophore based methods only focus on the chemical features about a molecule and are not capable of dealing with the molecular shape similarity. In order to evaluate the performance of molecular similarity based screening, many kinds of metrics are available, e.g., visual representation, quantitative measurements and scaffold hopping ability measurements. Further applications of molecular similarity include construction of molecule interaction network or generation of diverse compounds library.

Discovery of natural estrogen receptor modulators with structure-based virtual screening

Co-reporter:Xianwen Cao, Jing Jiang, Shoude Zhang, Lili Zhu, Juan Zou, Yanyan Diao, Weilie Xiao, Lei Shan, Handong Sun, Weidong Zhang, Jin Huang, Honglin Li

Bioorganic & Medicinal Chemistry Letters 2013 Volume 23(Issue 11) pp:3329-3333

Publication Date(Web):1 June 2013

DOI:10.1016/j.bmcl.2013.03.105

Eleven compounds were identified as estrogen receptor modulators from an in-house natural product database (NPD) by structure-based virtual screening for ERα and ERβ. Among them, 3 compounds were confirmed as ER agonists and 8 compounds were confirmed as ER antagonists by yeast two-hybrid (Y2H) assay, with EC50 values ranging from several micromolar to 100 micromolar. In this study, a novel series of cycloartane triterpenoids isolated from Schisandra glaucescens Diels was found to have ER antagonistic effect, the most potent antagonist of which exhibited activity with EC50 value of 2.55 and 4.68 μM for ERα and ERβ, respectively. Moreover, the types of modulation and subtype selectivity were also investigated through molecular docking simulation.

Discovery of novel inhibitors for human farnesyltransferase (hFTase) via structure-based virtual screening

Co-reporter:Xiaojuan Yu, Xue Zhao, Lili Zhu, Chuanxin Zou, Xiaofeng Liu, Zhenjiang Zhao, Jin Huang and Honglin Li

MedChemComm 2013 vol. 4(Issue 6) pp:962-971

Publication Date(Web):10 Apr 2013

DOI:10.1039/C3MD00058C

In this study, 22 novel hFTase inhibitors containing 18 scaffolds were identified with IC50 values ranging from 0.0119 to 13.35 μM by structure-based virtual screening, and compounds 2, 7, 9, 10, 14 and 15 showed moderate antiproliferative activity against MCF-7 cells. In particular, compound 2 was the most promising lead compound with nanomolar activity against FTase and antiproliferative activity in the low micromolar range. Possible binding modes of the hit compounds were explored and their structure–activity relationships (SAR) were elucidated by molecular docking simulation. The hit compounds discovered in this work will provide novel scaffolds for further hit-to-lead optimization and lay the foundation for further development of therapeutic candidates for cancer treatments.

Discovery of Diverse Human Dihydroorotate Dehydrogenase Inhibitors as Immunosuppressive Agents by Structure-Based Virtual Screening

Co-reporter:Yanyan Diao ; Weiqiang Lu ; Huangtao Jin ; Junsheng Zhu ; Le Han ; Minghao Xu ; Rui Gao ; Xu Shen ; Zhenjiang Zhao ; Xiaofeng Liu ; Yufang Xu ; Jin Huang

Journal of Medicinal Chemistry 2012 Volume 55(Issue 19) pp:8341-8349

Publication Date(Web):September 17, 2012

DOI:10.1021/jm300630p

This study applied an efficient virtual screening strategy integrating molecular docking with MM-GBSA rescoring to identify diverse human dihydroorotate dehydrogenase (hDHODH) inhibitors. Eighteen compounds with IC50 values ranging from 0.11 to 18.8 μM were identified as novel hDHODH inhibitors that exhibited overall species-selectivity over Plasmodium falciparum dihydroorotate dehydrogenase (pfDHODH). Compound 8, the most potent one, showed low micromolar inhibitory activity against hDHODH with an IC50 value of 0.11 μM. Moreover, lipopolysaccharide-induced B-cell assay and mixed lymphocyte reaction assay revealed that most of the hits showed potent antiproliferative activity against B and T cells, which demonstrates their potential application as immunosuppressive agents. In particular, compound 18 exhibited potent B-cell inhibitory activity (IC50 = 1.78 μM) and presents a B-cell-specific profile with 17- and 26-fold selectivities toward T and Jurkat cells, respectively.

Natural products as a gold mine for selective matrix metalloproteinases inhibitors

Co-reporter:Liyan Wang, Xi Li, Shoude Zhang, Weiqiang Lu, Sha Liao, Xiaofeng Liu, Lei Shan, Xu Shen, Hualiang Jiang, Weidong Zhang, Jin Huang, Honglin Li

Bioorganic & Medicinal Chemistry 2012 Volume 20(Issue 13) pp:4164-4171

Publication Date(Web):1 July 2012

DOI:10.1016/j.bmc.2012.04.063

Nineteen natural compounds with diverse structures are identified as potential MMPIs using structure-based virtual screening from 4000 natural products. Hydroxycinnamic acid or analogs of natural products are important for potent inhibitory and selectivity against MMPs, and the solvent effect in the S1′ pocket can affect the hydrophobic interactions and hydrogen bonds between MMPIs and MMPS, making MMPIs exhibit certain selectivity for a specific MMP isoenzyme. Furthermore, compound 5 can reduce the expression of both MMP-2 and active-MMP-9, and suppress the migration of MDA-MB-231 tumor cell in a wound healing assay, which may be further developed as an anticancer agent.

Discovery of novel selective inhibitors for EGFR-T790M/L858R

Co-reporter:Fang Bai, Hongyan Liu, Linjiang Tong, Wei Zhou, Li Liu, Zhenjiang Zhao, Xiaofeng Liu, Hualiang Jiang, Xicheng Wang, Hua Xie, Honglin Li

Bioorganic & Medicinal Chemistry Letters 2012 Volume 22(Issue 3) pp:1365-1370

Publication Date(Web):1 February 2012

DOI:10.1016/j.bmcl.2011.12.067

Through a receptor-based and ligand-based combined virtual screening protocol, 21 novel compounds covering 15 scaffolds were identified as novel inhibitors for EGFR-T790M/L858R, among which, 12 of them were identified as selective inhibitors for EGFR-T790M/L858R to wild-type EGFR, and 5 of them exhibited ‘dual-effective’ to wild-type and mutant EGFR. Meanwhile, their antiproliferative effects toward EGFR high-expressing human lung cancer cell (A549), epidermoid carcinoma cell (A431), and the mutant EGFR-dependent cell (NCI-H1975) were also evaluated.

Design and Synthesis of Small Molecule RhoA Inhibitors: A New Promising Therapy for Cardiovascular Diseases?

Co-reporter:Jing Deng ; Enguang Feng ; Sheng Ma ; Yan Zhang ; Xiaofeng Liu ; Honglin Li ; Huang Huang ; Jin Zhu ; Weiliang Zhu ; Xu Shen ; Liyan Miao ; Hong Liu ; Hualiang Jiang ;Jian Li

Journal of Medicinal Chemistry 2011 Volume 54(Issue 13) pp:4508-4522

Publication Date(Web):May 26, 2011

DOI:10.1021/jm200161c

RhoA is a member of Rho GTPases, a subgroup of the Ras superfamily of small GTP-binding proteins. RhoA, as an important regulator of diverse cellular signaling pathways, plays significant roles in cytoskeletal organization, transcription, and cell-cycle progression. The RhoA/ROCK inhibitors have emerged as a new promising treatment for cardiovascular diseases. However, to date, RhoA inhibitors are macromolecules, and to our knowledge, small molecular-based inhibitors have not been reported. In this study, a series of first-in-class small molecular RhoA inhibitors have been discovered by using structure-based virtual screening in conjunction with chemical synthesis and bioassay. Virtual screening of ∼200,000 compounds, followed by SPR-based binding affinity assays resulted in three compounds with binding affinities to RhoA at the micromolar level (compounds 1–3). Compound 1 was selected for further structure modifications in considering binding activity and synthesis ease. Fourty-one new compounds (1, 12a–v, 13a–h, and 14a–j) were designed and synthesized accordingly. It was found that eight (12a, 12j, 14a, 14b, 14d, 14e, 14 g, and 14h) showed high RhoA inhibition activities with IC50 values of 1.24 to 3.00 μM. A pharmacological assay indicated that two compounds (14g and 14 h) demonstrated noticeable vasorelaxation effects against PE-induced contraction in thoracic aorta artery rings and served as good leads for developing more potent cardiovascular agents.

SHAFTS: A Hybrid Approach for 3D Molecular Similarity Calculation. 2. Prospective Case Study in the Discovery of Diverse p90 Ribosomal S6 Protein Kinase 2 Inhibitors To Suppress Cell Migration

Co-reporter:Weiqiang Lu ; Xiaofeng Liu ; Xianwen Cao ; Mengzhu Xue ; Kangdong Liu ; Zhenjiang Zhao ; Xu Shen ; Hualiang Jiang ; Yufang Xu ; Jin Huang

Journal of Medicinal Chemistry 2011 Volume 54(Issue 10) pp:3564-3574

Publication Date(Web):April 13, 2011

DOI:10.1021/jm200139j

We described a prospective application of ligand-based virtual screening program SHAFTS to discover novel inhibitors for p90 ribosomal S6 protein kinase 2 (RSK2). Taking the putative 3D conformations of two weakly binding RSK2 NTKD inhibitors as query templates, SHAFTS was used to perform 3D similarity based virtual screening because of a lack of crystal structure of RSK2 protein, thus leading to the identification of several novel scaffolds that would have been missed by conventional 2D fingerprint methods. The most potent hit compounds show low micromolar inhibitory activities against RSK2. In particular, one of the hit compounds exhibits potent antimigration activity against the MDA-MB-231 tumor cell. The results exemplified SHAFTS’ application in active enrichment and scaffold hopping, which is of general interest for lead identification in drug discovery endeavors and also provides novel scaffolds that lay the foundation for uncovering new RSK2 regulatory mechanisms.

Accelerating All-Atom Normal Mode Analysis with Graphics Processing Unit

Co-reporter:Li Liu, Xiaofeng Liu, Jiayu Gong, Hualiang Jiang, and Honglin Li

Journal of Chemical Theory and Computation 2011 Volume 7(Issue 6) pp:1595-1603

Publication Date(Web):May 13, 2011

DOI:10.1021/ct100728k

All-atom normal mode analysis (NMA) is an efficient way to predict the collective motions in a given macromolecule, which is essential for the understanding of protein biological function and drug design. However, the calculations are limited in time scale mainly because the required diagonalization of the Hessian matrix by Householder-QR transformation is a computationally exhausting task. In this paper, we demonstrate the parallel computing power of the graphics processing unit (GPU) in NMA by mapping Householder-QR transformation onto GPU using Compute Unified Device Architecture (CUDA). The results revealed that the GPU-accelerated all-atom NMA could reduce the runtime of diagonalization significantly and achieved over 20× speedup over CPU-based NMA. In addition, we analyzed the influence of precision on both the performance and the accuracy of GPU. Although the performance of GPU with double precision is weaker than that with single precision in theory, more accurate results and an acceptable speedup of double precision were obtained in our approach by reducing the data transfer time to a minimum. Finally, the inherent drawbacks of GPU and the corresponding solution to deal with the limitation in computational scale are also discussed in this study.

SHAFTS: A Hybrid Approach for 3D Molecular Similarity Calculation. 1. Method and Assessment of Virtual Screening

Co-reporter:Xiaofeng Liu, Hualiang Jiang, and Honglin Li

Journal of Chemical Information and Modeling 2011 Volume 51(Issue 9) pp:2372-2385

Publication Date(Web):August 8, 2011

DOI:10.1021/ci200060s

We developed a novel approach called SHAFTS (SHApe-FeaTure Similarity) for 3D molecular similarity calculation and ligand-based virtual screening. SHAFTS adopts a hybrid similarity metric combined with molecular shape and colored (labeled) chemistry groups annotated by pharmacophore features for 3D similarity calculation and ranking, which is designed to integrate the strength of pharmacophore matching and volumetric overlay approaches. A feature triplet hashing method is used for fast molecular alignment poses enumeration, and the optimal superposition between the target and the query molecules can be prioritized by calculating corresponding “hybrid similarities”. SHAFTS is suitable for large-scale virtual screening with single or multiple bioactive compounds as the query “templates” regardless of whether corresponding experimentally determined conformations are available. Two public test sets (DUD and Jain’s sets) including active and decoy molecules from a panel of useful drug targets were adopted to evaluate the virtual screening performance. SHAFTS outperformed several other widely used virtual screening methods in terms of enrichment of known active compounds as well as novel chemotypes, thereby indicating its robustness in hit compounds identification and potential of scaffold hopping in virtual screening.

Discovery and SAR of Thiazolidine-2,4-dione Analogues as Insulin-like Growth Factor-1 Receptor (IGF-1R) Inhibitors via Hierarchical Virtual Screening

Co-reporter:Xiaofeng Liu ; Hua Xie ; Cheng Luo ; Linjiang Tong ; Yi Wang ; Ting Peng ; Jian Ding ; Hualiang Jiang

Journal of Medicinal Chemistry 2010 Volume 53(Issue 6) pp:2661-2665

Publication Date(Web):February 23, 2010

DOI:10.1021/jm901798e

Insulin-like growth factor-1 receptor (IGF-1R) is a growth factor receptor tyrosine kinase acting as a critical mediator of cell proliferation and survival. Novel 5-benzylidenethiazolidine-2,4-dione (5) and 5-(furan-2-ylmethylene)thiazolidine-2,4-dione (6) compounds were identified as potent and selective IGF-1R inhibitors via hierarchical virtual screening. Initial SAR and biological activity of the analogues of 5 and 6 with thiazolidine-2,4-dione template are presented, and several inhibitors with low nanomolar potency are reported.