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1.
Small molecule inhibitors of the MDM2-p53 interaction discovered by ensemble-based receptor models 总被引:1,自引:0,他引:1
Bowman AL Nikolovska-Coleska Z Zhong H Wang S Carlson HA 《Journal of the American Chemical Society》2007,129(42):12809-12814
Five nonpeptide, small-molecule inhibitors of the human MDM2-p53 interaction are presented, and each inhibitor represents a new scaffold. The most potent compound exhibited a Ki of 110 +/- 30 nM. These compounds were identified using our multiple protein structure (MPS) method which incorporates protein flexibility into a receptor-based pharmacophore model that identifies appropriate hotspots of binding. Docking the inhibitors with an induced-fit docking protocol suggested that the inhibitors mimicked the three critical binding residues of p53 (Phe19, Trp23, and Leu26). Docking also predicted a new orientation of the scaffolds that more fully fills the binding cleft, enabling the inhibitors to take advantage of additional hydrogen-bonding possibilities not explored by other small molecule inhibitors. One inhibitor in particular was proposed to probe the hydrophobic core of the protein by taking advantage of the flexibility of the binding cleft floor. These results show that the MPS technique is a promising advance for structure-based drug discovery and that the method can truly explore broad chemical space efficiently in the quest to discover potent, small-molecule inhibitors of protein-protein interactions. Our MPS technique is one of very few ensemble-based techniques to be proven through experimental verification of the discovery of new inhibitors. 相似文献
2.
Dr. Martin Peters Melanie Trobe Prof. Dr. Rolf Breinbauer 《Chemistry (Weinheim an der Bergstrasse, Germany)》2013,19(7):2450-2456
One of the most common protein–protein interactions (PPI) is the interaction of the α‐helix of one protein with the surface of the second one. Terphenylic scaffolds are bioinspired motifs in the inhibition of PPIs and have been identified as suitable α‐helix mimetics. One of the challenging aspects of this strategy is the poor solubility of terphenyls under physiological conditions. In the literature pyrrolopyrimidine‐, pyrimidine‐ or pyridazine‐based mimetics have been reported to show improved solubility. We present a new convergent strategy for the synthesis of linear pyridine‐type teraryls based on a phenylic core unit. A general approach for the synthesis of 3,5‐disubstituted pyridine‐based boronic acid pinacol esters with amino acid side chains in the 3‐position (representing Phe, Leu, Ile, Lys, Asp, Asn) is presented and exploits the functional group tolerance of the Knochel–Grignard reagents. The building blocks have been used in a convergent in situ two‐step synthesis of teraryl α‐helix mimetics. 相似文献
3.
Fang J Huang D Zhao W Ge H Luo HB Xu J 《Journal of chemical information and modeling》2011,51(6):1431-1438
Glycogen synthase kinase 3β (GSK-3β) is a potential therapeutic target for cancer, type-2 diabetes, and Alzheimer's disease. This paper proposes a new lead identification protocol that predicts new GSK-3β ATP competitive inhibitors with topologically diverse scaffolds. First, three-dimensional quantitative structure-activity relationship (3D QSAR) models were built and validated. These models are based upon known GSK-3β inhibitors, benzofuran-3-yl-(indol-3-yl) maleimides, by means of comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Second, 28?826 maleimide derivatives were selected from the PubChem database. After filtration via Lipinski's rules, 10?429 maleimide derivatives were left. Third, the FlexX-dock program was employed to virtually screen the 10?429 compounds against GSK-3β. This resulted in 617 virtual hits. Fourth, the 3D QSAR models predicted that from the 617 virtual hits, 93 compounds would have GSK-3β inhibition values of less than 15 nM. Finally, from the 93 predicted active hits, 23 compounds were confirmed as GSK-3β inhibitors from literatures; their GSK-3β inhibition ranged from 1.3 to 480 nM. Therefore, the hits rate of our virtual screening protocol is greater than 25%. The protocol combines ligand- and structure-based approaches and therefore validates both approaches and is capable of identifying new hits with topologically diverse scaffolds. 相似文献
4.
Bjoern A. Krueger Tanja Weil Gisbert Schneider 《Journal of computer-aided molecular design》2009,23(12):869-881
Identification of novel compound classes for a drug target is a challenging task for cheminformatics and drug design when
considerable research has already been undertaken and many potent lead structures have been identified, which leaves limited
unclaimed chemical space for innovation. We validated and successfully applied different state-of-the-art techniques for virtual
screening (Bayesian machine learning, automated molecular docking, pharmacophore search, pharmacophore QSAR and shape analysis)
of 4.6 million unique and readily available chemical structures to identify promising new and competitive antagonists of the
strychnine-insensitive Glycine binding site (GlycineB site) of the NMDA receptor. The novelty of the identified virtual hits was assessed by scaffold analysis, putting a strong
emphasis on novelty detection. The resulting hits were tested in vitro and several novel, active compounds were identified.
While the majority of the computational methods tested were able to partially discriminate actives from structurally similar
decoy molecules, the methods differed substantially in their prospective applicability in terms of novelty detection. The
results demonstrate that although there is no single best computational method, it is most worthwhile to follow this concept
of focused compound library design and screening, as there still can new bioactive compounds be found that possess hitherto
unexplored scaffolds and interesting variations of known chemotypes. 相似文献
5.
V. K. Vyas G. Qureshi M. Ghate H. Patel S. Dalai 《SAR and QSAR in environmental research》2016,27(6):427-440
Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) catalyses the fourth reaction of de novo pyrimidine biosynthesis in parasites, and represents an important target for the treatment of malaria. In this study, we describe pharmacophore-based virtual screening combined with docking study and biological evaluation as a rational strategy for identification of novel hits as antimalarial agents. Pharmacophore models were established from known PfDHODH inhibitors using the GALAHAD module with IC50 values ranging from 0.033 μM to 142 μM. The best pharmacophore model consisted of three hydrogen bond acceptor, one hydrogen bond donor and one hydrophobic features. The pharmacophore models were validated through receiver operating characteristic and Günere–Henry scoring methods. The best pharmacophore model as a 3D search query was searched against the IBS database. Several compounds with different structures (scaffolds) were retrieved as hit molecules. Among these compounds, those with a QFIT value of more than 81 were docked in the PfDHODH enzyme to further explore the binding modes of these compounds. In silico pharmacokinetic and toxicities were predicted for the best docked molecules. Finally, the identified hits were evaluated in vivo for their antimalarial activity in a parasite inhibition assay. The hits reported here showed good potential to become novel antimalarial agents. 相似文献
6.
Shah F Mukherjee P Gut J Legac J Rosenthal PJ Tekwani BL Avery MA 《Journal of chemical information and modeling》2011,51(4):852-864
Malaria, in particular that caused by Plasmodium falciparum , is prevalent across the tropics, and its medicinal control is limited by widespread drug resistance. Cysteine proteases of P. falciparum , falcipain-2 (FP-2) and falcipain-3 (FP-3), are major hemoglobinases, validated as potential antimalarial drug targets. Structure-based virtual screening of a focused cysteine protease inhibitor library built with soft rather than hard electrophiles was performed against an X-ray crystal structure of FP-2 using the Glide docking program. An enrichment study was performed to select a suitable scoring function and to retrieve potential candidates against FP-2 from a large chemical database. Biological evaluation of 50 selected compounds identified 21 diverse nonpeptidic inhibitors of FP-2 with a hit rate of 42%. Atomic Fukui indices were used to predict the most electrophilic center and its electrophilicity in the identified hits. Comparison of predicted electrophilicity of electrophiles in identified hits with those in known irreversible inhibitors suggested the soft-nature of electrophiles in the selected target compounds. The present study highlights the importance of focused libraries and enrichment studies in structure-based virtual screening. In addition, few compounds were screened against homologous human cysteine proteases for selectivity analysis. Further evaluation of structure-activity relationships around these nonpeptidic scaffolds could help in the development of selective leads for antimalarial chemotherapy. 相似文献
7.
Kanhaya Lal Rafael Bermeo Dr. Jonathan Cramer Prof. Dr. Francesca Vasile Prof. Dr. Beat Ernst Dr. Anne Imberty Prof. Dr. Anna Bernardi Dr. Annabelle Varrot Prof. Dr. Laura Belvisi 《Chemistry (Weinheim an der Bergstrasse, Germany)》2021,27(40):10341-10348
Burkholderia cenocepacia is an opportunistic Gram-negative bacterium that causes infections in patients suffering from chronic granulomatous diseases and cystic fibrosis. It displays significant morbidity and mortality due to extreme resistance to almost all clinically useful antibiotics. The bacterial lectin BC2L-C expressed in B. cenocepacia is an interesting drug target involved in bacterial adhesion and subsequent deadly infection to the host. We solved the first high resolution crystal structure of the apo form of the lectin N-terminal domain (BC2L-C-nt) and compared it with the ones complexed with carbohydrate ligands. Virtual screening of a small fragment library identified potential hits predicted to bind in the vicinity of the fucose binding site. A series of biophysical techniques and X-ray crystallographic screening were employed to validate the interaction of the hits with the protein domain. The X-ray structure of BC2L-C-nt complexed with one of the identified active fragments confirmed the ability of the site computationally identified to host drug-like fragments. The fragment affinity could be determined by titration microcalorimetry. These structure-based strategies further provide an opportunity to elaborate the fragments into high affinity anti-adhesive glycomimetics, as therapeutic agents against B. cenocepacia. 相似文献
8.
Hsieh JH Wang XS Teotico D Golbraikh A Tropsha A 《Journal of computer-aided molecular design》2008,22(9):593-609
9.
Wartchow CA Podlaski F Li S Rowan K Zhang X Mark D Huang KS 《Journal of computer-aided molecular design》2011,25(7):669-676
Biosensor-based fragment screening is a valuable tool in the drug discovery process. This method is advantageous over many
biochemical methods because primary hits can be distinguished from non-specific or non-ideal interactions by examining binding
profiles and responses, resulting in reduced false-positive rates. Biolayer interferometry (BLI), a technique that measures
changes in an interference pattern generated from visible light reflected from an optical layer and a biolayer containing
proteins of interest, is a relatively new method for monitoring small molecule interactions. The BLI format is based on a
disposable sensor that is immersed in 96-well or 384-well plates. BLI has been validated for small molecule detection and
fragment screening with model systems and well-characterized targets where affinity constants and binding profiles are generally
similar to those obtained with surface plasmon resonsance (SPR). Screens with challenging targets involved in protein–protein
interactions including BCL-2, JNK1, and eIF4E were performed with a fragment library of 6,500 compounds, and hit rates were
compared for these targets. For eIF4E, a protein containing a PPI site and a nucleotide binding site, results from a BLI fragment
screen were compared to results obtained in biochemical HTS screens. Overlapping hits were observed for the PPI site, and
hits unique to the BLI screen were identified. Hit assessments with SPR and BLI are described. 相似文献
10.
Trimerization of the HIV Transmembrane Domain in Lipid Bilayers Modulates Broadly Neutralizing Antibody Binding
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Dr. Timothy M. Reichart Dr. Michael M. Baksh Dr. Jin‐Kyu Rhee Dr. Jason D. Fiedler Prof. Dr. Stephen G. Sligar Prof. Dr. M. G. Finn Prof. Dr. Michael B. Zwick Prof. Dr. Philip E. Dawson 《Angewandte Chemie (International ed. in English)》2016,55(8):2688-2692
The membrane‐proximal external region (MPER) of HIV gp41 is an established target of antibodies that neutralize a broad range of HIV isolates. To evaluate the role of the transmembrane (TM) domain, synthetic MPER‐derived peptides were incorporated into lipid nanoparticles using natural and designed TM domains, and antibody affinity was measured using immobilized and solution‐based techniques. Peptides incorporating the native HIV TM domain exhibit significantly stronger interactions with neutralizing antibodies than peptides with a monomeric TM domain. Furthermore, a peptide with a trimeric, three‐helix bundle TM domain recapitulates the binding profile of the native sequence. These studies suggest that neutralizing antibodies can bind the MPER when the TM domain is a three‐helix bundle and this presentation could influence the binding of neutralizing antibodies to the virus. Lipid‐bilayer presentation of viral antigens in Nanodiscs is a new platform for evaluating neutralizing antibodies. 相似文献
11.
Carboxyltransferase domain(CT) of acetyl-coenzyme A carboxylase(ACCase, EC 6.4.1.2) from a family of Poaceae is an important target of commercial herbicide APPs for controlling grass weed growth. As the abuse of APPs herbicides, the resistant ACCase due to the mutation of a single residue(Ile→Leu), which is lo-cated in CT active site, is emergent in many populations and species of Poaceae. So it is urgent to understand the re-sistant mecha-nism so as to design new effect herbicides. Herein lies the complex of CT dimmer from Lolium rigi-dum and herbicide haloxyfop successfully constructed for wild type enzyme and Ile/Leu mutant, respectively, pro-viding a basis for explaining the resistance from microscopic structure. Moreover, the binding free energy difference between wild type and mutant enzymes was predicted in good agreement with the known observation, and the various contributions to it were analyzed, by Molecular mechanics-Poisson-Boltzmann surface area(MM-PBSA) method. The results indicate the van der Waals interaction difference between the protein and inhibitor, –22.94 kJ/mol of CT wild type lower than that of mutant, is the major reason for resistance. Structure analysis further suggests that van der Waals interaction difference is originated from the steric hindrance between the side chain of mutated residue Leu and the chiral methyl group of haloxyfop. All these findings enhance the understanding of resistant mechanism of ACCase to herbicide by Ile/Leu mutation and provide an important clue for the rational design of high effective herbicides. 相似文献
12.
Jun-Jiang Lv Yan Liu Xiao-Yan Zeng Jia Yu Yan Li Xiao-Qin Du Zhong-Bao Wu Shi-Lei Hao Bo-Chu Wang 《Molecules (Basel, Switzerland)》2021,26(24)
Red deer (Cervus elaphus) blood is widely used as a health product. Mixed culture fermentation improves the flavor and bioavailability of deer blood (DB), and both DB and its enzymatic hydrolysates exhibit anti-fatigue activities in vivo. To elucidate the bioactive ingredients, enzymatic hydrolysates were fractioned into different peptide groups using reversed phase resin chromatography, and then evaluated using an exhaustive swimming mice model to assess swimming time and biochemical parameters. The structures of the bioactive peptides were elucidated by high performance liquid chromatography with tandem mass detection. Thirty-one compounds were identified as glutamine or branched-chain amino acids containing short peptides, of which Val-Ala-Asn, Val-Val-Ser-Ala, Leu(Ile)-Leu(Ile)-Val-Thr, Pro-His-Pro-Thr-Thr, Glu-Val-Ala-Phe and Val-Leu(Ile)-Asp-Ala-Phe are new peptides. The fractions containing glutamine or valine short peptides, Ala-Gln, Val-Gln, Val-Val-Ser-Ala, Val-Leu(Ile)-Ser improved exercise endurance by increasing hepatic glycogen (HG) storage. The peptides group containing Leu(Ile)-Leu(Ile), Asp-Gln, Phe- Leu(Ile), Val-Val-Tyr-Pro contributed to decreased muscle lactic acid (MLA)accumulation and to an increase in HG. The anti-fatigue activities of DB hydrolysates were attributed to the synergistic effects of different types of peptides. 相似文献
13.
Metz M Bourque E Labrecque J Danthi SJ Langille J Harwig C Yang W Darkes MC Lau G Santucci Z Bridger GJ Schols D Fricker SP Skerlj RT 《Journal of the American Chemical Society》2011,133(41):16477-16485
The viral resistance of marketed antiviral drugs including the emergence of new viral resistance of the only marketed CCR5 entry inhibitor, maraviroc, makes it necessary to develop new CCR5 allosteric inhibitors. A mutagenesis/modeling approach was used (a) to remove the potential hERG liability in an otherwise very promising series of compounds and (b) to design a new class of compounds with an unique mutant fingerprint profile depending on residues in the N-terminus and the extracellular loop 2. On the basis of residues, which were identified by mutagenesis as key interaction sites, binding modes of compounds were derived and utilized for compound design in a prospective manner. The compounds were then synthesized, and in vitro evaluation not only showed that they had good antiviral potency but also fulfilled the requirement of low hERG inhibition, a criterion necessary because a potential approved drug would be administered chronically. This work utilized an interdisciplinary approach including medicinal chemistry, molecular biology, and computational chemistry merging the structural requirements for potency with the requirements of an acceptable in vitro profile for allosteric CCR5 inhibitors. The obtained mutant fingerprint profiles of CCR5 inhibitors were used to translate the CCR5 allosteric binding site into a general pharmacophore, which can be used for discovering new inhibitors. 相似文献
14.
Prof. Dr. Masayuki Endo Yosuke Takeuchi Tomoko Emura Kumi Hidaka Prof. Dr. Hiroshi Sugiyama 《Chemistry (Weinheim an der Bergstrasse, Germany)》2014,20(47):15330-15333
In nucleic acid nanotechnology, designed RNA molecules are widely explored because of their usability originating from RNA’s structural and functional diversity. Herein, a method to design and prepare RNA nanostructures by employing DNA origami strategy was developed. A single‐stranded RNA scaffold and staple RNA strands were used for the formation of RNA nanostructures. After the annealing of the mixtures, 7‐helix bundled RNA tile and 6‐helix bundled RNA tube structures were observed as predesigned shapes. These nanostructures were easily functionalized by introducing chemical modification to the RNA scaffolds. The DNA origami method is extended and utilized to construct RNA nanostructures. 相似文献
15.
Two New Cyclic Tetrapeptides of Streptomyces rutgersensis T009 Isolated from Elaphodus davidianus Excrement
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Shu‐Quan Li Ya‐Bin Yang Xue‐Qiong Yang Yi Jiang Zhen‐Jie Li Xiao‐Zhan Li Xiu Chen Qi‐Lin Li Shao‐Huan Qin Zhong‐Tao Ding 《Helvetica chimica acta》2016,99(3):210-214
Two new cyclic tetrapeptides, cyclo(l ‐Val‐l ‐Leu‐l ‐Val‐l ‐Ile) ( 1 ) and cyclo(l ‐Leu‐l ‐Leu‐l ‐Ala‐l ‐Ala) ( 2 ), and 15 known compounds, cyclo(Gly‐l ‐Leu‐Gly‐l ‐Leu) ( 3 ), cyclo(l ‐Ser‐l ‐Phe) ( 4 ), cyclo(l ‐Leu‐l ‐Ile) ( 5 ), cyclo(l ‐Tyr‐l ‐Phe) ( 6 ), cyclo(Gly‐l ‐Trp) ( 7 ), cyclo(l ‐Leu‐l ‐Tyr) ( 8 ), cyclo(Gly‐l ‐Phe) ( 9 ), cyclo(l ‐Phe‐trans‐4‐hydroxy‐l ‐Pro) ( 10 ), cyclo(l ‐Leu‐l ‐Leu) ( 11 ), cyclo(l ‐Val‐l ‐Phe) ( 12 ), cyclo(l ‐Val‐l ‐Leu) ( 13 ), cyclo(l ‐Ile‐l ‐Ile) ( 14 ), cyclo(l ‐Tyr‐l ‐Tyr) ( 15 ), turnagainolide A ( 16 ), and bacimethrin ( 17 ) were isolated from the fermentation broth of Streptomyces rutgersensis T009 obtained from Elaphodus davidianus excrement. Their structures were identified on the basis of spectroscopic analysis. Meanwhile, the absolute configurations of the amino acid residues of compounds 1 and 2 were determined by advanced Marfey method. Compound 3 was obtained from a natural source for the first time. The X‐ray single crystal diffraction data of bacimethrin ( 17 ) were also reported for the first time. Compounds 1 – 17 exhibited no antimicrobial activities with the MICs > 100 μg/ml. 相似文献
16.
Supriyo Bhattacharya Govindan Subramanian Spencer Hall Jianping Lin Abdelazize Laoui Nagarajan Vaidehi 《Journal of computer-aided molecular design》2010,24(8):659-674
The 41 amino acid neuropeptide, corticotropin-releasing factor (CRF) and its associated receptors CRF1-R and CRF2-R have been targeted for treating stress related disorders. Both CRF1-R and CRF2-R belong to the class B G-protein coupled receptors for which little information is known regarding the small molecule antagonist
binding characteristics. However, it has been shown recently that different non-peptide allosteric ligands stabilize different
receptor conformations for CRF1-R and hence an understanding of the ligand induced receptor conformational changes is important in the pharmacology of ligand
binding. In this study, we modeled the receptor and identified the binding sites of representative small molecule allosteric
antagonists for CRF1-R. The predicted binding sites of the investigated compounds are located within the transmembrane (TM) domain encompassing
TM helices 3, 5 and 6. The docked compounds show strong interactions with H228 on TM3 and M305 on TM5 that have also been
implicated in the binding by site directed mutation studies. H228 forms a hydrogen bond of varied strengths with all the antagonists
in this study and this is in agreement with the decreased binding affinity of several compounds with H228F mutation. Also
mutating M305 to Ile showed a sharp decrease in the calculated binding energy whereas the binding energy loss on M305 to Leu
was less significant. These results are in qualitative agreement with the decrease in binding affinities observed experimentally.
We further predicted the conformational changes in CRF1-R induced by the allosteric antagonist NBI-27914. Movement of TM helices 3 and 5 are dominant and generates three degenerate
conformational states two of which are separated by an energy barrier from the third, when bound to NBI-27914. Binding of
NBI-27914 was predicted to improve the interaction of the ligand with M305 and also enhanced the aromatic stacking between
the ligand and F232 on TM3. A virtual ligand screening of ~13,000 compounds seeded with ~350 CRF1-R specific active antagonists performed on the NBI-27914 stabilized conformation of CRF1-R yielded a 44% increase in enrichment compared to the initially modeled receptor conformation at a 10% cutoff. The NBI-27914
stabilized conformation also shows a high enrichment for high affinity antagonists compared to the weaker ones. Thus, the
conformational changes induced by NBI-27914 improved the ligand screening efficiency of the CRF1-R model and demonstrate a generalized application of the method in drug discovery. 相似文献
17.
Costa M Areias F Castro M Brea J Loza MI Proença F 《Organic & biomolecular chemistry》2011,9(11):4242-4249
A one-pot procedure was developed for the synthesis of novel 3-[amino(methoxy)methylene]-2-oxo-3,4-dihydro-2H-chromen-4-yl)-3-cyanoacetamides and chromeno[3,4-c]pyridine-1-carbonitriles from the reaction of 2-oxo-2H-chromene-3-carbonitriles and cyanoacetamides. These chromene derivatives were identified as new scaffolds for adenosine receptors and the hits 3a, 3c, 5a, and 5b were found. 相似文献
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20.
Brady RM Hatzis E Connor T Street IP Baell JB Lessene G 《Organic & biomolecular chemistry》2012,10(27):5230-5237
The design of small molecules that mimic the BH3 domain and bind to Bcl-2 proteins has emerged as a promising approach to discovering novel anti-cancer therapeutics. We reveal the design and synthesis of conformationally constrained benzoylurea scaffolds as conformational probes. Central to helix mimicry, the intramolecular hydrogen bond in the benzoylurea plays a key role in the pre-organisation of the acyclic substrates for cyclisation via ring closing metathesis, providing efficient access to the constrained mimetics. 相似文献