Publications by authors named "Weiliang Zhu"

272 Publications

Pterostilbene inhibits hepatocellular carcinoma proliferation and HBV replication by targeting ribonucleotide reductase M2 protein.

Am J Cancer Res 2021 15;11(6):2975-2989. Epub 2021 Jun 15.

Department of Pathology & Pathophysiology, and Cancer Institute of The Second Affiliated Hospital, Zhejiang University School of Medicine Hangzhou, China.

Hepatocellular carcinoma (HCC), one of the most deadly diseases all around the world. HBV infection is a causative factor of HCC and closely associated with HCC development. Ribonucleotide reductase (RR) is a key enzyme for cellular DNA synthesis and RR small subunit M2 (RRM2) is highly upregulated in HCC with poor survival rates. We have previously shown that HBV can activate the expression of RRM2 and the activity of RR enzyme for the viral DNA replication in host liver cells. Thus, RRM2 may be an important therapeutic target for HCC and HBV-related HCC. Pterostilbene, a natural plant component, potently inhibited RR enzyme activity with the IC of about 0.62 μM through interacting with RRM2 protein, which was much higher than current RRM2 inhibitory drugs. Pterostilbine inhibited cell proliferation with an MTT IC of about 20-40 μM in various HCC cell lines, causing DNA synthesis inhibition, cell cycle arrest at S phase, and accordingly apoptosis. On the other hand, the compound significantly inhibited HBV DNA replication in HBV genome integrated and newly transfected HCC cells, and the EC for inhibiting HBV replication was significantly lower than the IC for inhibiting HCC proliferation. Notably, pterostilbene possessed a similar inhibitory activity in sorafenib and lamivudine resistant HCC cells. Moreover, the inhibitory effects of pterostilbine against HCC proliferation and HBV replication were significantly reversed by addition of dNTP precursors, suggesting that RR was the intracellular target of the compound. Finally, pterostilbine effectively inhibited HCC xenograft growth with a relatively low toxicity in nude mouse experiments. This study demonstrates that pterostilbene is a novel potent RR inhibitor by targeting RRM2. It can simultaneously inhibit HCC proliferation and HBV replication with a potential new use for treatment of HCC and HBV-related HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263682PMC
June 2021

Glycosides from with their protective effects on photoreceptor cells in light-damaged mouse retinas.

Nat Prod Res 2021 Jun 26:1-9. Epub 2021 Jun 26.

CAS Key Laboratory of Receptor Research; Drug Discovery and Design Centre, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

A new phenylethanoid, hebitol IV (), along with fifteen known glycosides (), were isolated from water extract of the flower buds of . Their structures were elucidated on the basis of 1 D-NMR, 2 D-NMR and MS data. Molecular docking showed the potential activities of the natural products against VEGFR-2. Bioassay results revealed that the compounds and exhibited strong inhibitory activity against VEGFR-2 with IC values of 0.51 and 0.32 μM, respectively. Moreover, the potential retinal protective effects of and were then investigated in the mouse model featuring bright light-induced retinal degeneration. The results demonstrated remarkable photoreceptor protective activities of and .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14786419.2021.1944138DOI Listing
June 2021

Catenin Alpha-2 Mutation Changes the Immune Microenvironment in Lung Adenocarcinoma Patients Receiving Immune Checkpoint Inhibitors.

Front Pharmacol 2021 7;12:645862. Epub 2021 Jun 7.

Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.

Lung cancer has always been the most prevalent cancer. Lung adenocarcinoma (LUAD) is the most common lung cancer subtype and has a high tumor mutation rate. In addition to KRAS, EGFR, ALK, HER2, ROS1, and BRAF, which are known to have high mutation rates, we discovered some new mutated genes, such as catenin alpha-2 (CTNNA2), in LUAD patients treated with immune checkpoint inhibitors (ICIs). These mutant genes are potential therapeutic targets for LUAD. We analyzed a cohort of LUAD patients with somatic mutation and survival data in the Cancer Genome Atlas (TCGA) database and a cohort of LUAD patients receiving immune checkpoint inhibitors with clinical data and whole-exome sequencing (WES) mutation data to evaluate the role of CTNNA2 gene mutation in LUAD. In addition, CIBERSORT was used to analyze the immune characteristics of CTNNA2 wild-type patients and CTNNA2 mutant-type patients, and gene set enrichment analysis (GSEA) was employed for pathway enrichment analysis. The results were verified by downloading data regarding the drug sensitivity of LUAD cell lines from the Genomics of Drug Sensitivity in Cancer (GDSC) database. We found that CTNNA2 mutation was associated with longer overall survival (OS) in LUAD patients. Analysis of the cohort from the Cancer Genome Atlas showed that patients with CTNNA2 mutation had more tumor neoantigens and a greater tumor mutation burden (TMB). Through further analysis of the tumor immune microenvironment, we found that in LUAD patients with CTNNA2 mutations, the gene expression levels of chemokine C-X-C motif chemokine 9 (CXCL9) and granzyme B (GZMB) were elevated, and the gene expression level of inhibitory receptor killer cell immunoglobulin-like receptor 2DL1 (KIR2DL1) was significantly reduced. These alterations might affect gene expression in macrophages, NK cells, and mast cell markers. In addition, LUAD patients with CTNNA2 mutation had a significantly increased number of mutations in DNA damage response (DDR) genes. The drug susceptibility results and gene set enrichment analysis showed that after CTNNA2 mutation occurred, changes were found in the DNA damage response pathway, the phosphoinositide 3-kinase (PI3K) pathway and others, indicating that CTNNA2 mutation can regulate the activation of PI3K and DDR pathways. Our findings provide novel insights into the underlying pathogenesis of LUAD. CTNNA2 mutation can change the immune microenvironment, thereby improving patient prognosis. The results also suggest that CTNNA2 may become a new biomarker and therapeutic target for LUAD in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2021.645862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215613PMC
June 2021

Discovery of chiral N-2'-aryletheryl-1'-alkoxy-ethyl substituted arylisoquinolones with anti-inflammatory activity from the nucleophilic addition reactions of the thiophenols and oxazolinium.

Eur J Med Chem 2021 Jun 1;222:113583. Epub 2021 Jun 1.

CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China. Electronic address:

Herein we disclosed the novel nucleophilic addition reactions of the thiophenols and oxazolinium (DCZ0358) to produce N-2'-aryletheryl-1'-alkoxy-ethyl substituted arylisoquinolones. After evaluating the anti-inflammatory activity in vitro, 2d was found having significant anti-TNFα activity. Through the amplified synthesis of 2d, four monomers (3a-b and 4a-d) were obtained by chiral separation of the product. The reaction mechanism was proposed and explored by the control experiments. However, only the R-stereoisomers 3b and 4b have significant anti-TNFα activity in vitro (IC = 56 and 14 nM, respectively). Moreover, 4b exerts potent therapeutic effects on ulcerative colitis in vivo (30 mg/kg bw, qd, i. g.). The subsequent bio-target exploration of compound 4bvia molecular docking and the experimental validation disclosed that 4b has 3-fold selectivity of binding activity on estrogen receptor (ER) beta (β) (Ki = 760.86 nM) vs. alpha (α) (Ki = 2320.58 nM). Thus, it provides a novel type of non-steroidal leads for developing anti-inflammatory drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2021.113583DOI Listing
June 2021

A novel phosphoramide compound, DCZ0805, shows potent anti-myeloma activity via the NF-κB pathway.

Cancer Cell Int 2021 May 30;21(1):285. Epub 2021 May 30.

CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.

Background: Multiple myeloma (MM) is a highly aggressive and incurable clonal plasma cell disease with a high rate of recurrence. Thus, the development of new therapies is urgently needed. DCZ0805, a novel compound synthesized from osalmide and pterostilbene, has few observed side effects. In the current study, we intend to investigate the therapeutic effects of DCZ0805 in MM cells and elucidate the molecular mechanism underlying its anti-myeloma activity.

Methods: We used the Cell Counting Kit-8 assay, immunofluorescence staining, cell cycle assessment, apoptosis assay, western blot analysis, dual-luciferase reporter assay and a tumor xenograft mouse model to investigate the effect of DCZ0805 treatment both in vivo and in vitro.

Results: The results showed that DCZ0805 treatment arrested the cell at the G0/G1 phase and suppressed MM cells survival by inducing apoptosis via extrinsic and intrinsic pathways. DCZ0805 suppressed the NF-κB signaling pathway activation, which may have contributed to the inhibition of cell proliferation. DCZ0805 treatment remarkably reduced the tumor burden in the immunocompromised xenograft mouse model, with no obvious toxicity observed.

Conclusion: The findings of this study indicate that DCZ0805 can serve as a novel therapeutic agent for the treatment of MM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12935-021-01973-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165811PMC
May 2021

D3DistalMutation: a Database to Explore the Effect of Distal Mutations on Enzyme Activity.

J Chem Inf Model 2021 05 2;61(5):2499-2508. Epub 2021 May 2.

CAS Key Laboratory of Receptor Research; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Enzyme activity is affected by amino acid mutations, particularly mutations near the active site. Increasing evidence has shown that distal mutations more than 10 Å away from the active site may significantly affect enzyme activity. However, it is difficult to study the enzyme regulation mechanism of distal mutations due to the lack of a systematic collection of three-dimensional (3D) structures, highlighting distal mutation site and the corresponding enzyme activity change. Therefore, we constructed a distal mutation database, namely, D3DistalMutation, which relates the distal mutation to enzyme activity. As a result, we observed that approximately 80% of distal mutations could affect enzyme activity and 72.7% of distal mutations would decrease or abolish enzyme activity in D3DistalMutation. Only 6.6% of distal mutations in D3DistalMutation could increase enzyme activity, which have great potential to the industrial field. Among these mutations, the Y to F, S to D, and T to D mutations are most likely to increase enzyme activity, which sheds some light on industrial catalysis. Distal mutations decreasing enzyme activity in the allosteric pocket play an indispensable role in allosteric drug design. In addition, the pockets in the enzyme structures are provided to explore the enzyme regulation mechanism of distal mutations. D3DistalMutation is accessible free of charge at https://www.d3pharma.com/D3DistalMutation/index.php.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jcim.1c00318DOI Listing
May 2021

Identification and mechanistic analysis of an inhibitor of the CorC Mg transporter.

iScience 2021 Apr 26;24(4):102370. Epub 2021 Mar 26.

State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Shanghai Key Laboratory of Bioactive Small Molecules, Department of Physiology and Biophysics, School of Life Sciences, Fudan University, 2005 Songhu Road, Yangpu District, Shanghai 200438, China.

The CorC/CNNM family of Na-dependent Mg transporters is ubiquitously conserved from bacteria to humans. CorC, the bacterial CorC/CNNM family of proteins, is involved in resistance to antibiotic exposure and in the survival of pathogenic microorganisms in their host environment. The CorC/CNNM family proteins possess a cytoplasmic region containing the regulatory ATP-binding site. CorC and CNNM have attracted interest as therapeutic targets, whereas inhibitors targeting the ATP-binding site have not been identified. Here, we performed a virtual screening of CorC by targeting its ATP-binding site, identified a compound named IGN95a with inhibitory effects on ATP binding and Mg export, and determined the cytoplasmic domain structure in complex with IGN95a. Furthermore, a chemical cross-linking experiment indicated that with ATP bound to the cytoplasmic domain, the conformational equilibrium of CorC was shifted more toward the inward-facing state of the transmembrane domain. In contrast, IGN95a did not induce such a shift.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.isci.2021.102370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066426PMC
April 2021

Anti-DLBCL efficacy of DCZ0825 in vitro and in vivo: involvement of the PI3K‒AKT‒mTOR/JNK pathway.

Acta Biochim Biophys Sin (Shanghai) 2021 Apr;53(5):575-583

Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, characterized by high heterogeneity. The poor outcome of a portion of patients who suffer relapsing or resistant to conventional treatment impels the development of novel agents for DLBCL. DCZ0825 is a novel compound derived from pterostilbene and osalmide, whose antitumor activities have drawn our attention. In this study, we found that DCZ0825 exhibited high cytotoxicity toward DLBCL cell lines in a dose- and time-dependent manner, as revealed by cell counting kit-8 assay. Flow cytometry and western blot analysis results showed that DCZ0825 also promoted cell apoptosis via both extrinsic and intrinsic apoptosis pathways mediated by caspase. In addition, DCZ0825 induced cell cycle arrest in the G2/M phase by downregulating Cdc25C, CDK1, and Cyclin B1, thus interfering with cell proliferation. Further investigation showed the involvement of the phosphatidylinositol 3-kinase (PI3K)‒AKT‒mTOR/JNK pathway in the efficacy of DCZ0825 against DLBCL. Remarkably, DCZ0825 also exerted notable cytotoxic effects in vivo as well, with low toxicity to important internal organs such as the liver and kidney. Our results suggest that DCZ0825 may have the potential to become a novel anti-DLBCL agent or to replenish the conventional therapeutic scheme of DLBCL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/abbs/gmab031DOI Listing
April 2021

Structural basis for the Mg recognition and regulation of the CorC Mg transporter.

Sci Adv 2021 Feb 10;7(7). Epub 2021 Feb 10.

State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Bioactive Small Molecules, Collaborative Innovation Center of Genetics and Development, and Department of Physiology and Biophysics, School of Life Sciences, Fudan University, 2005 Songhu Road, Yangpu District, Shanghai 200438, China.

The CNNM/CorC family proteins are Mg transporters that are widely distributed in all domains of life. In bacteria, CorC has been implicated in the survival of pathogenic microorganisms. In humans, CNNM proteins are involved in various biological events, such as body absorption/reabsorption of Mg and genetic disorders. Here, we determined the crystal structure of the Mg-bound CorC TM domain dimer. Each protomer has a single Mg binding site with a fully dehydrated Mg ion. The residues at the Mg binding site are strictly conserved in both human CNNM2 and CNNM4, and many of these residues are associated with genetic diseases. Furthermore, we determined the structures of the CorC cytoplasmic region containing its regulatory ATP-binding domain. A combination of structural and functional analyses not only revealed the potential interface between the TM and cytoplasmic domains but also showed that ATP binding is important for the Mg export activity of CorC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.abe6140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875539PMC
February 2021

One step stereoselective synthesis of oxazoline-fused saccharides and their conversion into the corresponding 1,2- glycosylamines bearing various protected groups.

Org Biomol Chem 2021 02;19(7):1580-1588

Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China. and CAS Key Laboratory of Receptor Research; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. and School of Pharmacy, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.

Herein we disclosed a straightforward synthesis of oxazoline-fused saccharides (oxazolinoses) from peracetylated saccharides and benzonitriles under acidic conditions with stoichiometric amounts of water. The density functional theory (DFT) calculations have revealed the origin of the stereoselectivity and the key role of water in promoting the departure of the acetyl group at C-2. The resulting oxazolinoses can be concisely converted into the corresponding 1,2-cis glycosylamines bearing various protected groups, allowing the access to schisandrin derivatives.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0ob02477eDOI Listing
February 2021

Ligand-based approach for predicting drug targets and for virtual screening against COVID-19.

Brief Bioinform 2021 03;22(2):1053-1064

Shanghai Institute of Materia Medica in 1998.

Discovering efficient drugs and identifying target proteins are still an unmet but urgent need for curing coronavirus disease 2019 (COVID-19). Protein structure-based docking is a widely applied approach for discovering active compounds against drug targets and for predicting potential targets of active compounds. However, this approach has its inherent deficiency caused by e.g. various different conformations with largely varied binding pockets adopted by proteins, or the lack of true target proteins in the database. This deficiency may result in false negative results. As a complementary approach to the protein structure-based platform for COVID-19, termed as D3Docking in our previous work, we developed in this study a ligand-based method, named D3Similarity, which is based on the molecular similarity evaluation between the submitted molecule(s) and those in an active compound database. The database is constituted by all the reported bioactive molecules against the coronaviruses, viz., severe acute respiratory syndrome coronavirus (SARS), Middle East respiratory syndrome coronavirus (MERS), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human betacoronavirus 2c EMC/2012 (HCoV-EMC), human CoV 229E (HCoV-229E) and feline infectious peritonitis virus (FIPV), some of which have target or mechanism information but some do not. Based on the two-dimensional (2D) and three-dimensional (3D) similarity evaluation of molecular structures, virtual screening and target prediction could be performed according to similarity ranking results. With two examples, we demonstrated the reliability and efficiency of D3Similarity by using 2D × 3D value as score for drug discovery and target prediction against COVID-19. The database, which will be updated regularly, is available free of charge at https://www.d3pharma.com/D3Targets-2019-nCoV/D3Similarity/index.php.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/bib/bbaa422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929377PMC
March 2021

Increasing the Sampling Efficiency of Protein Conformational Change by Combining a Modified Replica Exchange Molecular Dynamics and Normal Mode Analysis.

J Chem Theory Comput 2021 Jan 22;17(1):13-28. Epub 2020 Dec 22.

CAS Key Laboratory of Receptor Research; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.

Understanding conformational change at an atomic level is significant when determining a protein functional mechanism. Replica exchange molecular dynamics (REMD) is a widely used enhanced sampling method to explore protein conformational space. However, REMD with an explicit solvent model requires huge computational resources, immensely limiting its application. In this study, a variation of parallel tempering metadynamics (PTMetaD) with the omission of solvent-solvent interactions in exchange attempts and the use of low-frequency modes calculated by normal-mode analysis (NMA) as collective variables (CVs), namely ossPTMetaD, is proposed with the aim to accelerate MD simulations simultaneously in temperature and geometrical spaces. For testing the performance of ossPTMetaD, five protein systems with diverse biological functions and motion patterns were selected, including large-scale domain motion (AdK), flap movement (HIV-1 protease and BACE1), and DFG-motif flip in kinases (p38α and c-Abl). The simulation results showed that ossPTMetaD requires much fewer numbers of replicas than temperature REMD (T-REMD) with a reduction of ∼70% to achieve a similar exchange ratio. Although it does not obey the detailed balance condition, ossPTMetaD provides consistent results with T-REMD and experimental data. The high accessibility of the large conformational change of protein systems by ossPTMetaD, especially in simulating the very challenging DFG-motif flip of protein kinases, demonstrated its high efficiency and robustness in the characterization of the large-scale protein conformational change pathway and associated free energy profile.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jctc.0c00592DOI Listing
January 2021

Computational Insights into the Conformational Accessibility and Binding Strength of SARS-CoV-2 Spike Protein to Human Angiotensin-Converting Enzyme 2.

J Phys Chem Lett 2020 Dec 4;11(24):10482-10488. Epub 2020 Dec 4.

CAS Key Laboratory of Receptor Research; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

The spike protein of SARS-CoV-2 (CoV-2-S) mediates the virus entry into human cells. Experimental studies have shown the stronger binding affinity of the RBD (receptor binding domain) of CoV-2-S to angiotensin-converting enzyme 2 (ACE2) as compared to that of SARS-CoV spike (CoV-S). However, a similar or weaker binding affinity of CoV-2-S compared to that of CoV-S is observed if entire spikes are used in the bioassay. To explore the underlying mechanism, we calculated the binding affinities of the RBDs to ACE2 and simulated the transitions between ACE2-inaccessible and -accessible conformations. We found that the ACE2-accessible angle of CoV-2-S is 52.2° and that the ACE2 binding strength of CoV-2-S RBD is much stronger than that of CoV-S RBD. However, CoV-2-S has much less of an ACE2-accessible conformation and is much more difficult to shift from ACE2-inaccessible to -accessible than CoV-S, making the binding affinity of the entire protein decrease. Further analysis revealed key interactional residues for strong binding and five potential ligand-binding pockets for drug research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jpclett.0c02958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737396PMC
December 2020

Substitution Effect of the Trifluoromethyl Group on the Bioactivity in Medicinal Chemistry: Statistical Analysis and Energy Calculations.

J Chem Inf Model 2020 12 1;60(12):6242-6250. Epub 2020 Dec 1.

The Key Laboratory of Plant Resources and Chemistry in Arid Regions and Key Laboratory of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, South Beijing Road 40-1, Urumqi, Xinjiang 830011, People's Republic of China.

The substitution of methyl (Me or -CH) by trifluoromethyl (TFM or -CF) is frequently used in medicinal chemistry. However, the exact effect of -CH/-CF substitution on bioactivity is still controversial. We compiled a data set containing 28 003 pairs of compounds with the only difference that -CH is substituted by -CF, and the statistical results showed that the replacement of -CH with -CF does not improve bioactivity on average. Yet, 9.19% substitution of -CH by -CF could increase the biological activity by at least an order. A PDB survey revealed that -CF prefers Phe, Met, Leu, and Tyr, while -CH prefers Leu, Met, Cys, and Ile. If we substitute the -CH by -CF near Phe, His, and Arg, the bioactivity is most probably improved. We performed QM/MM calculations for 39 -CH/-CF pairs of protein-ligand complexes and found that the -CH/-CF substitution does achieve a large energy gain in some systems, although the mean energy difference is subtle, which is consistent with the statistical survey. The -CF substitution on the benzene ring could be particularly effective at gaining binding energy. The maximum improvements in energy achieved -4.36 kcal/mol by QM/MM calculation. Moreover, energy decompositions from MM/GBSA calculations showed that the large energy gains for the -CH/-CF substitution are largely driven by the electrostatic energy or the solvation free energy. These findings may shed some light on the biological activity profile for -CH/-CF substitution, which should be useful for further drug discovery and drug design.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jcim.0c00898DOI Listing
December 2020

DCZ3301, an aryl-guanidino agent, inhibits ocular neovascularization via PI3K/AKT and ERK1/2 signaling pathways.

Exp Eye Res 2020 12 26;201:108267. Epub 2020 Sep 26.

Eye Institute, Eye & ENT Hospital, Shanghai Medical College, Fudan University, NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, And Shanghai Key Laboratory of Visual Impairment and Restoration (Fudan University), Shanghai, China. Electronic address:

Neovascularization is a critical process in the pathophysiology of neovascular eye diseases. Although anti-VEGF therapy has achieved remarkable curative effects, complications, limited efficacy and drug resistance remain the prominent problems. DCZ3301, an aryl-guanidino compound, was reported to have anti-tumor activity in the previous studies. Here, we demonstrated the effects of DCZ3301 on human umbilical vein endothelial cell (HUVEC) in vitro, and performed choroid microvascular sprouting assay ex vivo and alkali-burn induced corneal neovascularization mouse model in vivo. We found that DCZ3301 inhibited the proliferation, migration, and tube formation of HUVECs, while inducing the spontaneous apoptosis of HUVECs by suppressing the activation of PI3K/AKT and ERK1/2 pathways. Furthermore, DCZ3301 inhibited the choroid microvascular sprouting, diminished the area of corneal neovascularization and attenuated the edema of corneal stroma after alkali burn. Together, these results suggested that DCZ3301 exerted anti-angiogenic properties, and might be regarded as a potential candidate for ocular neovascularization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.exer.2020.108267DOI Listing
December 2020

Synthesis and Structure-Activity Relationships of 3-Arylisoquinolone Analogues as Highly Specific hCES2A Inhibitors.

ChemMedChem 2021 Jan 22;16(2):388-398. Epub 2020 Oct 22.

Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China.

Mammalian carboxylesterases (CES) are key enzymes that participate in the hydrolytic metabolism of various endogenous and exogenous substrates. Human carboxylesterase 2A (hCES2A), mainly distributed in the small intestine and colon, plays a significant role in the hydrolysis of many drugs. In this study, 3-arylisoquinolones 3 h [3-(4-(benzyloxy)-3-methoxyphenyl)-7,8-dimethoxyisoquinolin-1(2H)-one] and 4 a [3-(4-(benzyloxy)-3-methoxyphenyl)-4-bromo-7,8-dimethoxyisoquinolin-1(2H)-one] were found to have potent inhibitory effects on hCES2A (IC =0.68 μΜ, K =0.36 μΜ) and excellent specificity (more than 147.05-fold over hCES1 A). Moreover, 4 a exhibited threefold improved inhibition on intracellular hCES2A in living HepG2 cells relative to 3 h, with an IC value of 0.41 μΜ. Results of inhibition kinetics studies and molecular docking simulations demonstrate that both 3 h and 4 a can bind to multiple sites on hCES2A, functioning as mixed inhibitors. Structure-activity relationship analysis revealed that the lactam moiety on the B ring is crucial for specificity towards hCES2A, while a benzyloxy group is optimal for hCES2A inhibitory potency; the introduction of a bromine atom may enhance cell permeability, thereby increasing the intracellular hCES2A inhibitory activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cmdc.202000581DOI Listing
January 2021

Computational study of the substituent effect of halogenated fused-ring heteroaromatics on halogen bonding.

J Mol Model 2020 Sep 15;26(10):270. Epub 2020 Sep 15.

CAS Key Laboratory of Receptor Research; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.

Halogen bonding (XB) has been applied in many fields from crystal engineering to medicinal chemistry. Compared with the well-studied XB of simple halogenated aromatics, little research has been done on the XB of halogenated fused-ring heteroaromatics, a prevalent substructure in organic compounds. With 1H-pyrrolo[3,2-b]pyridines (PPs) as examples of novel fused-ring heteroaromatics with hydrogen bond donor and acceptor and XB donor, the XB formed by the halogenated heteroaromatics was explored in this study. With 4 different substituents, viz., -CH, -NH, -F, and -CONH, at different positions, 339 derivatives of brominated PP (Br-PP) were designed for calculating their electrostatic potential of the σ-hole of the halogen atom (V) and binding energy with ammonia as XB acceptor (E) at M06-2X/6-311++G(d,p) level by PCM model in dichloromethane. The calculated V values ranging from -1.3 to 35.1 kcal/mol and the calculated E ranging from -0.82 to -2.37 kcal/mol demonstrated that the XB is complicated and highly tunable. Noticeably, the electron-withdrawing substituents, especially at ortho-position, do not always increase the values of V, while the electron-donating substituents do not always decrease V. Similar results were observed from the calculation on 339 iodinated PPs at M06-2X/6-311++G(d,p) level. The complexity of the XB formed by the halogenated fused ring heteroaromatics indicated a great potential of tuning its strength by different substituents at different positions and revealed a necessity of quantum chemistry calculation for predicting the XB.Graphical abstract.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00894-020-04534-xDOI Listing
September 2020

Unveiling conformational dynamics changes of H-Ras induced by mutations based on accelerated molecular dynamics.

Phys Chem Chem Phys 2020 Sep;22(37):21238-21250

Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.

Uncovering molecular basis with regard to the conformational change of two switches I and II in the GppNHp (GNP)-bound H-Ras is highly significant for the understanding of Ras signaling. For this purpose, accelerated molecular dynamics (aMD) simulations and principal component (PC) analysis are integrated to probe the effect of mutations G12V, T35S and Q61K on conformational transformation between two switches of the GNP-bound H-Ras. The RMSF and cross-correlation analyses suggest that three mutations exert a vital effect on the flexibility and internal dynamics of two switches in the GNP-bound H-Ras. The results stemming from PC analysis indicate that two switches in the GNP-bound WT H-Ras tend to form a closed state in most conformations, while those in the GNP-bound mutated H-Ras display transformation between different states. This conclusion is further supported by free energy landscapes constructed by using the distances of residues 12 away from 35 and 35 away from 61 as reaction coordinates and different experimental studies. Interaction scanning is performed on aMD trajectories and the information shows that conformational transformations of two switches I and II induced by mutations extremely affect the GNP-residue interactions. Meanwhile, the scanning results also signify that residues G15, A18, F28, K117, A146 and K147 form stable contacts with GNP, while residues D30, E31, Y32, D33, P34 and E62 in two switches I and II produce unstable contacts with GNP. This study not only reveals dynamic behavior changes of two switches in H-Ras induced by mutations, but also unveils general principles and mechanisms with regard to functional conformational changes of H-Ras.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0cp03766dDOI Listing
September 2020

Identification of a novel CpG methylation signature to predict prognosis in lung squamous cell carcinoma.

Cancer Biomark 2021 ;30(1):63-73

Department of Oncology, Zhu Jiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

Background: DNA methylation plays a vital role in modulating genomic function and warrants evaluation as a biomarker for the diagnosis and treatment of lung squamous cell carcinoma (LUSC).

Objective: In this study, we aimed to identify effective potential biomarkers for predicting prognosis and drug sensitivity in LUSC.

Methods: A univariate Cox proportional hazards regression analysis, a random survival forests-variable hunting (RSFVH) algorithm, and a multivariate Cox regression analysis were adopted to analyze the methylation profile of patients with LUSC included in public databases: The Cancer Genome Atlas (TCGA), and the Gene Expression Omnibus (GEO).

Results: A methylated region consisting of 3 sites (cg06675147, cg07064331, cg20429172) was selected. Patients were divided into a high-risk group and a low-risk group in the training dataset. High-risk patients had shorter overall survival (OS) (hazard ratio [HR]: 2.72, 95% confidence interval [CI]: 1.82-4.07, P< 0.001) compared with low-risk patients. The accuracy of the prognostic signature was validated in the test and validation cohorts (TCGA, n= 94; GSE56044, n= 23). Gene set variation analysis (GSVA) showed that activity in the cell cycle/mitotic, ERBB, and ERK/MAPK pathways was higher in the high-risk compared with the low-risk group, which may lead to differences in OS.Interestingly, we observed that patients in the high-risk group were more sensitive to gemcitabine and docetaxel than the low-risk group, which is consistent with results of the GSVA.

Conclusion: We report novel methylation sites that could be used as powerful tools for predicting risk factors for poorer survival in patients with LUSC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/CBM-201564DOI Listing
January 2021

Prognosis of Lung Adenocarcinoma Patients With NTRK3 Mutations to Immune Checkpoint Inhibitors.

Front Pharmacol 2020 12;11:1213. Epub 2020 Aug 12.

Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.

Background: Immune checkpoint inhibitors (ICIs) are an important treatment modality that must be considered for patients with lung adenocarcinoma (LUAD). However, ICIs are effective only in some of these patients. Therefore, identifying biomarkers that accurately predict the prognosis of patients with LUAD treated with ICIs can help maximize their therapeutic benefits. This study aimed to identify a new potential predictor to better select and optimally benefit LUAD patients.

Methods: We first collected and analyzed a discovery immunotherapy cohort comprising clinical and mutation data for LUAD patients. Then, we evaluated whether the specific mutated genes can act as predictive biomarkers in this discovery immunotherapy cohort and further validated the findings in The Cancer Genome Atlas (TCGA) project LUAD cohort. Gene set enrichment analysis (GSEA) was used to explore possible alterations in DNA damage response (DDR) pathways within the gene mutation. Moreover, we analyzed whole-exome sequencing (WES) and drug sensitivity response data for LUAD cell lines in the Genomics of Drug Sensitivity in Cancer (GDSC) database.

Results: Among the mutated genes screened from both the ICI treatment and TCGA-LUAD cohorts, NTRK3 mutation (mutant-type NTRK3, NTRK3-MT) was strongly associated with immunotherapy. First, significant differences in overall survival (OS) were observed between patients with NTRK3-MT and those with NTRK3-WT in the ICI treatment cohort but not in the non-ICI-treated TCGA-LUAD cohort. We then analyzed the association of NTRK3-MT with clinical characteristics and found the tumor mutation burden (TMB) to be significantly higher in both NTRK3-MT cohorts. However, significant differences in neoantigen levels and smoking history were found only for NTRK3-MT in the LUAD cohort from TCGA. Furthermore, some immune-related genes and immune cell-related genes were significantly upregulated in patients with NTRK3-MT compared to those with NTRK3-WT. In addition, NTRK3 mutation affected the deregulation of some signaling pathways and the DDR pathway.

Conclusions: Our findings suggest that NTRK3-MT can predict the prognosis of patients with LUAD treated by ICIs and that it may have clinical significance for immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2020.01213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434857PMC
August 2020

Phenols and γ-Lactams from the Aerial Part of Pseudolysimachion linariifolium subsp. dilatatum.

Chem Biodivers 2020 Oct 24;17(10):e2000387. Epub 2020 Sep 24.

School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, P. R. China.

Linariifolioside II (1) and (2S)-2-hydroxy-5-oxoproline methyl ester (2), two new compounds along with 13 known compounds were obtained from the aerial part of Pseudolysimachion linariifolium Holub subsp. dilatatum (Nakai & Kitag.) D.Y. Hong. Their chemical structures were revealed mainly through NMR and MS data. The absolute configuration of 2 was deduced by comparing its experimental CD with the calculated ECD spectra. At a concentration of 1 mm, total antioxidant capacities of compounds 1-15 were measured using a rapid ABTS method in vitro. Compounds 1, 3-5, and 11-14 exhibited approximately equal antioxidant capacity to that of vitamin C (Vc).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cbdv.202000387DOI Listing
October 2020

EPHA5 mutation predicts the durable clinical benefit of immune checkpoint inhibitors in patients with lung adenocarcinoma.

Cancer Gene Ther 2020 Aug 6. Epub 2020 Aug 6.

Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.

Immune checkpoint inhibitor (ICI) therapy has shown remarkable clinical benefit in lung adenocarcinoma (LUAD) patients. Genomic mutations may be applicable to predict the response to ICIs. Eph receptor A5 (EPHA5) is frequently mutated in breast cancer, lung cancer, and other tumors; however, its association with outcome in patients who receive immunotherapy remains unknown. In this study, we report that EPHA5 mutations were associated with increased tumor mutation burden (TMB), neoantigen load, levels of immune-related gene expression signatures, and enhanced tumor-infiltrating lymphocytes (TILs) in LUAD. LUAD patients with EPHA5 mutations in the immunotherapy cohort achieved a longer progression-free survival (PFS) time than patients with wild-type EPHA5. Immune response pathways were among the top enriched pathways in samples with EPHA5 mutations. In addition, patients with EPHA5 mutations tended to be more sensitive to certain targeted molecular inhibitors, including serdemetan, lox2, and PF1-1. Collectively, our results suggest that identifying mutations in the EPHA5 gene may provide insight into the genome-wide mutational burden and may serve as a biomarker to predict the immune response of patients with LUAD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41417-020-0207-6DOI Listing
August 2020

ZFHX3 mutation as a protective biomarker for immune checkpoint blockade in non-small cell lung cancer.

Cancer Immunol Immunother 2021 Jan 11;70(1):137-151. Epub 2020 Jul 11.

Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Gongye Road, Guangzhou, 510282, People's Republic of China.

To date, immunotherapy has opened a new chapter in the treatment of lung cancer. Precise biomarkers can help to screen subpopulations of lung cancer to provide the best treatment. Multiple studies suggest that specific gene mutations may be predictive markers in guiding non-small cell lung cancer (NSCLC) immune checkpoint inhibitor (ICI) treatment. A published immunotherapy cohort with mutational and survival data for 350 NSCLC patients was used. First, the mutational data of the immunotherapy cohort were used to identify gene mutations related to the prognosis of ICI therapy. The immunotherapy cohort and TCGA-NSCLC cohort were further studied to elucidate the relationships between specific gene mutations and tumor immunogenicity, antitumor immune response capabilities, and immune cell and mutation counts in the DNA damage response (DDR) pathway. In the immunotherapy cohort (N = 350), ZFHX3 mutations were an independent predictive biomarker for NSCLC patients receiving ICI treatment. Significant differences were observed between ZFHX3-mutant (ZFHX3-MT) and ZFHX3-wild type (ZFHX3-WT) patients regarding the overall survival (OS) time (P < 0.001, HR = 0.26, 95% Cl 0.17-0.41). ZFHX3-MT is significantly associated with higher tumor mutation burden (TMB) and neoantigen load (NAL), and ZFHX3-MT positively correlates with known immunotherapy response biomarkers, including T-cell infiltration, immune-related gene expression, and mutation counts in the DDR pathway in NSCLC. ZFHX3-MT is closely related to longer OS in NSCLC patients treated with ICIs, suggesting that ZFHX3 mutations be used as a novel predictive marker in guiding NSCLC ICI treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00262-020-02668-8DOI Listing
January 2021

Glycolysis is suppressed by DCZ0801-induced inactivation of the Akt/mTOR pathway in Multiple Myeloma.

J Cancer 2020 15;11(16):4907-4916. Epub 2020 Jun 15.

CAS Key Laboratory of Receptor Research; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Multiple myeloma (MM) is a highly invasive and incurable plasma cell malignant disease with frequent recurrence. DCZ0801 is a natural compound synthesized from osalmide and pterostilbene and has few adverse effects. Here, we aimed to observe the therapeutic effects of DCZ0801 on myeloma cells and clarify the specific molecular mechanism underlying its anti-tumor activity. The Cell Counting Kit-8 assay, apoptosis detection, cell cycle analysis, western blot analysis, and tumor xenograft models were used to determine the effect of DCZ0801 treatment both and . We revealed that DCZ0801 treatment suppressed MM cell survival by inducing apoptosis and blocking the cell cycle at S phase. Deranged glycolysis and downregulated Akt/mTOR pathway may also be responsible for cell proliferation inhibition. Moreover, DCZ0801 treatment could remarkably reduce the tumor size in the xenograft mouse model. Therefore these findings indicate that DCZ0801 can be used as a novel therapeutic drug for patients suffering from multiple myeloma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/jca.45146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330679PMC
June 2020

A novel M phase blocker, DCZ3301 enhances the sensitivity of bortezomib in resistant multiple myeloma through DNA damage and mitotic catastrophe.

J Exp Clin Cancer Res 2020 Jun 9;39(1):105. Epub 2020 Jun 9.

Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China.

Background: DCZ3301, a novel aryl-guanidino compound previously reported by our group, exerts cytotoxic effects against multiple myeloma (MM), diffused large B cell lymphoma (DLBCL), and T-cell leukemia/lymphoma. However, the underlying mechanism of its action remains unknown.

Methods: We generated bortezomib (BTZ)-resistant cell lines, treated them with various concentrations of DCZ3301 over varying periods, and studied its effect on colony formation, cell proliferation, apoptosis, cell cycle, DNA synthesis, and DNA damage response. We validated our results using in vitro and in vivo experimental models.

Results: DCZ3301 overcame bortezomib (BTZ) resistance through regulation of the G/M checkpoint in multiple myeloma (MM) in vitro and in vivo. Furthermore, treatment of BTZ-resistant cells with DCZ3301 restored their drug sensitivity. DCZ3301 induced M phase cell cycle arrest in MM mainly via inhibiting DNA repair and enhancing DNA damage. Moreover, DCZ3301 promoted the phosphorylation of ATM, ATR, and their downstream proteins, and these responses were blocked by the ATM specific inhibitor KU55933.

Conclusions: Our study provides a proof-of-concept that warrants the clinical evaluation of DCZ3301 as a novel anti-tumor compound against BTZ resistance in MM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13046-020-01597-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285565PMC
June 2020

Kinesin family members KIF2C/4A/10/11/14/18B/20A/23 predict poor prognosis and promote cell proliferation in hepatocellular carcinoma.

Am J Transl Res 2020 15;12(5):1614-1639. Epub 2020 May 15.

Department of Oncology, Zhujiang Hospital, Southern Medical University 253 Industrial Avenue, Guangzhou 510282, China.

Kinesin superfamily proteins (KIFs) comprise a family of molecular motors that transport membranous organelles and protein complexes in a microtubule- and ATP-dependent manner, with multiple roles in cancers. Little is known about the function of KIFs in hepatocellular carcinoma (HCC). Here, we investigate the roles of KIFs in the prognosis and progression of HCC. Upregulation of eight KIFs (KIF2C, KIF4A, KIF10, KIF11, KIF14, KIF18B, KIF20A, and KIF23) was found to be significantly associated with the tumor stage and pathological tumor grade of HCC patients. Additionally, a high expression of these eight KIFs was significantly associated with shorter overall survival (OS) and disease-free survival (DFS) in patients with HCC. Cox regression analysis showed the mRNA expression levels of these eight KIF members to be independent prognostic factors for worse outcomes in HCC. Moreover, a risk score model based on the mRNA levels of the eight KIF members effectively predicted the OS rate of patients with HCC. Additional experiments revealed that downregulation of each of the eight KIFs effectively decreased the proliferation and increased the G1 arrest of liver cancer cells in vitro. Taken together, these results indicate that KIF2C/4A/10/11/14/18B/20A/23 may serve as prognostic biomarkers for survival and potential therapeutic targets in HCC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270015PMC
May 2020

Bisindole alkaloids with nitric oxide inhibitory activities from an alcohol extract of the Isatis indigotica roots.

Fitoterapia 2020 Oct 2;146:104654. Epub 2020 Jun 2.

School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People's Republic of China. Electronic address:

Eight bisindole alkaloids including six undescribed ones (1a/1b-5) were isolated from an alcohol extract of the Isatis indigotica roots. Their structures and absolute configurations were supported by extensive spectroscopic data analysis, including 1D, 2D NMR, HRESIMS data, specific rotation data, and comparison of the experimental and calculated ECD data. Compounds 1a and 1b were determined to be a pair of enantiomers with a ratio of approximately 1:1 by chiral-phase chromatography analysis while compound 4 was elucidated as a new type of bisindole alkaloid with the aglycone categorized as bis(indole-1'/3″-yl)methane. All the isolated compounds were tested for their nitric oxide (NO) inhibitory effects and 1-4 and 6 exhibited inhibitory effects with IC values ranging from 11.0 to 37.6 μM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.fitote.2020.104654DOI Listing
October 2020

Interaction Nature and Computational Methods for Halogen Bonding: A Perspective.

J Chem Inf Model 2020 06 8;60(6):2683-2696. Epub 2020 Jun 8.

CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Halogen bonds are noncovalent interactions that have been widely used in many fields, including drug design, crystal engineering, and material sciences. A clear understanding of the nature of halogen bonding as well as the proper theoretical bonding description, especially the development of efficient and accurate computational chemical methods and their application in complex systems, is of great significance to promote the development of related fields. In this perspective, we reviewed the investigations of the nature of halogen bonding in recent years and discussed the development of quantum mechanical, molecular mechanical, and empirical scoring function methods in properly describing halogen-bonding interactions, as well as their achievements in corresponding areas. An evaluation on the performance of various quantum mechanical and semiempirical quantum mechanical methods in describing halogen bonds was also included, involving the DFT-D4 scheme and the recently reported xTB methods. We hope this perspective may be helpful, from the insights of computational tools and methods, in providing reference and enlightenment for the application of halogen bonds in fields like high-throughput virtual screening and rational drug design.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jcim.0c00032DOI Listing
June 2020

Accurate prediction of relative binding affinities of a series of HIV-1 protease inhibitors using semi-empirical quantum mechanical charge.

J Comput Chem 2020 07 30;41(19):1773-1780. Epub 2020 Apr 30.

CAS Key Laboratory of Receptor Research; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, China.

A major challenge in computer-aided drug design is the accurate estimation of ligand binding affinity. Here, a new approach that combines the adaptive steered molecular dynamics (ASMD) and partial atomic charges calculated by semi-empirical quantum mechanics (SQMPC), namely ASMD-SQMPC, is suggested to predict the ligand binding affinities, with 24 HIV-1 protease inhibitors as testing examples. In the ASMD-SQMPC, the relative binding free energy (ΔG) is reflected by the average maximum potential of mean force ( ) between bound and unbound states. The correlation coefficient (R ) between the and experimentally determined ΔG is 0.86, showing a significant improvement compared with the conventional ASMD (R = 0.52). Therefore, this study provides an efficient approach to predict the relative ΔG and reveals the significance of precise partial atomic charges in the theoretical simulations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcc.26218DOI Listing
July 2020

D3Targets-2019-nCoV: a webserver for predicting drug targets and for multi-target and multi-site based virtual screening against COVID-19.

Acta Pharm Sin B 2020 Jul 20;10(7):1239-1248. Epub 2020 Apr 20.

CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

A highly effective medicine is urgently required to cure coronavirus disease 2019 (COVID-19). For the purpose, we developed a molecular docking based webserver, namely D3Targets-2019-nCoV, with two functions, one is for predicting drug targets for drugs or active compounds observed from clinic or / studies, the other is for identifying lead compounds against potential drug targets docking. This server has its unique features, (1) the potential target proteins and their different conformations involving in the whole process from virus infection to replication and release were included as many as possible; (2) all the potential ligand-binding sites with volume larger than 200 Å on a protein structure were identified for docking; (3) correlation information among some conformations or binding sites was annotated; (4) it is easy to be updated, and is accessible freely to public (https://www.d3pharma.com/D3Targets-2019-nCoV/index.php). Currently, the webserver contains 42 proteins [20 severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) encoded proteins and 22 human proteins involved in virus infection, replication and release] with 69 different conformations/structures and 557 potential ligand-binding pockets in total. With 6 examples, we demonstrated that the webserver should be useful to medicinal chemists, pharmacologists and clinicians for efficiently discovering or developing effective drugs against the SARS-CoV-2 to cure COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.apsb.2020.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169934PMC
July 2020
-->