Application of MM-GB/SA and WaterMap to SRC Kinase Inhibitor Potency Prediction.

abstract：:The renal outer medullary potassium channel (ROMK or Kir1.1) is a putative drug target for a novel class of diuretics that could be used for the treatment of hypertension and edematous states such as heart failure. An internal high-throughput screening campaign identified 1,4-bis(4-nitrophenethyl)piperazine (5) as a p...

journal_title：ACS medicinal chemistry letters

authors： Tang H,Walsh SP,Yan Y,de Jesus RK,Shahripour A,Teumelsan N,Zhu Y,Ha S,Owens KA,Thomas-Fowlkes BS,Felix JP,Liu J,Kohler M,Priest BT,Bailey T,Brochu R,Alonso-Galicia M,Kaczorowski GJ,Roy S,Yang L,Mills SG,Garcia M

更新日期：2012-03-28 00:00:00

abstract：:In addition to its therapeutic value as a chemotherapy drug, gemcitabine is of ongoing interest to the scientific community for its broad-spectrum antiviral activity. Herein the synthesis of 4'-methoxy- and 4'-fluoro-substituted gemcitabine analogues along with their phosphoramidate prodrugs is described. Among these ...

journal_title：ACS medicinal chemistry letters

authors： Zheng Z,Groaz E,Snoeck R,De Jonghe S,Herdewijn P,Andrei G

更新日期：2020-12-09 00:00:00

abstract：:DNA methylation is known as the prima donna epigenetic mark for its critical role in regulating local gene transcription. Changes in the landscape of DNA methylation across the genome occur during cellular transition, such as differentiation and altered neuronal plasticity, and become dysregulated in disease states su...

journal_title：ACS medicinal chemistry letters

authors： Chua GNL,Wassarman KL,Sun H,Alp JA,Jarczyk EI,Kuzio NJ,Bennett MJ,Malachowsky BG,Kruse M,Kennedy AJ

更新日期：2019-01-31 00:00:00

abstract：:Toxoplasma gondii causes a prevalent human infection for which only the acute stage has an FDA-approved therapy. To find inhibitors of both the acute stage parasites and the persistent cyst stage that causes a chronic infection, we repurposed a compound library containing known inhibitors of parasitic hexokinase, the ...

journal_title：ACS medicinal chemistry letters

authors： Khalifa MM,Martorelli Di Genova B,McAlpine SG,Gallego-Lopez GM,Stevenson DM,Rozema SD,Monaghan NP,Morris JC,Knoll LJ,Golden JE

更新日期：2020-10-13 00:00:00

abstract：:The attachment of lipids to C- or N-terminally positioned lysine side-chain amino groups increases the activity of a short synthetic (Arg-Trp)3 antimicrobial peptide significantly, making these peptides even active against pathogenic Gram-negative bacteria. Thus, a peptide with strong activity against S. aureus (1.1-2...

journal_title：ACS medicinal chemistry letters

authors： Albada HB,Prochnow P,Bobersky S,Langklotz S,Schriek P,Bandow JE,Metzler-Nolte N

更新日期：2012-09-04 00:00:00

abstract：:Protein thermal shift assays (TSAs) provide a means for characterizing target engagement through ligand-induced thermal stabilization. Although these assays are widely utilized for screening libraries and validating hits in drug discovery programs, they can impose encumbering operational requirements, such as the avai...

journal_title：ACS medicinal chemistry letters

authors： Dart ML,Machleidt T,Jost E,Schwinn MK,Robers MB,Shi C,Kirkland TA,Killoran MP,Wilkinson JM,Hartnett JR,Zimmerman K,Wood KV

更新日期：2018-04-16 00:00:00

abstract：:Activating mutations in the epidermal growth factor receptor (EGFR) have been identified in a subset of non-small cell lung cancer (NSCLC), which is one of the leading cancer types worldwide. Application of EGFR tyrosine kinase inhibitors leads to acquired resistance by secondary EGFR mutations or by amplification of ...

journal_title：ACS medicinal chemistry letters

authors： Szokol B,Gyulavári P,Kurkó I,Baska F,Szántai-Kis C,Greff Z,Orfi Z,Peták I,Pénzes K,Torka R,Ullrich A,Orfi L,Vántus T,Kéri G

更新日期：2014-01-30 00:00:00

abstract：:A new class of potent matrix metalloproteinase (MMP) inhibitors designed by structure-based optimization of the well-known arylsulfonamide scaffold is presented. Molecules show an ethylene linker connecting the sulfonamide group with the P1' aromatic portion and a d-proline residue bearing the zinc-binding group. The ...

journal_title：ACS medicinal chemistry letters

authors： Mori M,Massaro A,Calderone V,Fragai M,Luchinat C,Mordini A

更新日期：2013-05-14 00:00:00

abstract：:Thirty-two diverse compounds were evaluated for their ability to inhibit both Pgp-mediated efflux in mouse T-lymphoma L5178 MDR1 and NorA-mediated efflux in S. aureus SA-1199B. Only four compounds were strong inhibitors of both efflux pumps. Three compounds were found to inhibit Pgp exclusively and strongly, while sev...

journal_title：ACS medicinal chemistry letters

authors： Brincat JP,Broccatelli F,Sabatini S,Frosini M,Neri A,Kaatz GW,Cruciani G,Carosati E

更新日期：2012-01-23 00:00:00

abstract：:Structural modifications to the coumarin core and benzamide side chain of novobiocin have successfully transformed the natural product from a selective DNA gyrase inhibitor into a potent inhibitor of the Hsp90 C-terminus. However, no SAR studies have been conducted on the noviose appendage, which represents the rate-l...

journal_title：ACS medicinal chemistry letters

authors： Zhao H,Kusuma BR,Blagg BS

更新日期：2010-07-13 00:00:00

abstract：:A high throughput screen was developed to identify novel, nonsteroidal RORα agonists. Among the validated hit compounds, the 4-(4-(benzyloxy)phenyl)-5-carbonyl-2-oxo-1,2,3,4-tetrahydropyrimidine scaffold was the most prominent. Among the numerous analogues tested, compounds 8 and 9 showed the highest activity. Key str...

journal_title：ACS medicinal chemistry letters

authors： Dubernet M,Duguet N,Colliandre L,Berini C,Helleboid S,Bourotte M,Daillet M,Maingot L,Daix S,Delhomel JF,Morin-Allory L,Routier S,Walczak R

更新日期：2013-04-10 00:00:00

abstract：:With only two new classes of antibiotics developed in the last 40 years, novel antibiotics are desperately needed to combat the growing problem of multidrug-resistant and extensively drug resistant bacteria, particularly Gram-negative bacteria. Described in this letter is the synthesis and antibiotic activity of 1,2,4...

journal_title：ACS medicinal chemistry letters

authors： Huggins WM,Minrovic BM,Corey BW,Jacobs AC,Melander RJ,Sommer RD,Zurawski DV,Melander C

更新日期：2016-11-12 00:00:00

abstract：:An electrostatic interaction related to a favorable position of the distal phenyl ring and a phenylalanine residue in the binding pocket would explain the higher 5-HT1A affinity of a 4-phenyl-1,2,3,6-tetrahydropyridine (THP) analogue compared to the corresponding 4-phenylpiperazine analogue. To explore a possible rein...

journal_title：ACS medicinal chemistry letters

authors： Liégeois JF,Lespagnard M,Meneses Salas E,Mangin F,Scuvée-Moreau J,Dilly S

更新日期：2014-01-29 00:00:00

abstract：:A series of N-acylbenzenesulfonamide dihydro-1,3,4-oxadiazole hybrids (EMAC8000a-m) was designed and synthesized with the aim to target tumor associated carbonic anhydrase (hCA) isoforms IX and XII. Most of the compounds were selective inhibitors of the tumor associated hCA XII. Moreover, resolution of EMAC8000d racem...

journal_title：ACS medicinal chemistry letters

authors： Bianco G,Meleddu R,Distinto S,Cottiglia F,Gaspari M,Melis C,Corona A,Angius R,Angeli A,Taverna D,Alcaro S,Leitans J,Kazaks A,Tars K,Supuran CT,Maccioni E

更新日期：2017-06-21 00:00:00

abstract：:[This corrects the article DOI: 10.1021/acsmedchemlett.9b00612.]. ...

journal_title：ACS medicinal chemistry letters

authors： Kaiser TM,Dentmon ZW,Dalloul CE,Sharma SK,Liotta DC

更新日期：2020-06-24 00:00:00

abstract：:Novel sources of antibiotics are needed to address the serious threat of bacterial resistance. Accordingly, we have launched a structure-based drug design program featuring a desmethylation strategy wherein methyl groups have been replaced with hydrogens. Herein we report the total synthesis, molecular modeling, and b...

journal_title：ACS medicinal chemistry letters

authors： Glassford I,Lee M,Wagh B,Velvadapu V,Paul T,Sandelin G,DeBrosse C,Klepacki D,Small MC,MacKerell AD Jr,Andrade RB

更新日期：2014-07-16 00:00:00

abstract：:The identification of Pim-1/2 kinase overexpression in B-cell malignancies suggests that Pim kinase inhibitors will have utility in the treatment of lymphoma, leukemia, and multiple myeloma. Starting from a moderately potent quinoxaline-dihydropyrrolopiperidinone lead, we recognized the potential for macrocyclization ...

journal_title：ACS medicinal chemistry letters

authors： Cee VJ,Chavez F Jr,Herberich B,Lanman BA,Pettus LH,Reed AB,Wu B,Wurz RP,Andrews KL,Chen J,Hickman D,Laszlo J 3rd,Lee MR,Guerrero N,Mattson BK,Nguyen Y,Mohr C,Rex K,Sastri CE,Wang P,Wu Q,Wu T,Xu Y,Zhou Y,Wi

更新日期：2016-02-12 00:00:00

abstract：:Inhibition of phosphoinositide 3-kinase (PI3K) signaling is an appealing approach to treat brain tumors, especially glioblastoma multiforme (GBM). We previously disclosed our successful approach to prospectively design potent and blood-brain barrier (BBB) penetrating PI3K inhibitors. The previously disclosed molecules...

journal_title：ACS medicinal chemistry letters

authors： Heffron TP,Ndubaku CO,Salphati L,Alicke B,Cheong J,Drobnick J,Edgar K,Gould SE,Lee LB,Lesnick JD,Lewis C,Nonomiya J,Pang J,Plise EG,Sideris S,Wallin J,Wang L,Zhang X,Olivero AG

更新日期：2016-02-16 00:00:00

abstract：:Heat shock protein 90 (Hsp90) is a molecular chaperone that is responsible for the folding and maturation of client proteins that are associated with all ten hallmarks of cancer. Hsp90 N-terminal pan inhibitors have experienced unfavorable results in clinical trials due to induction of the heat shock response (HSR), a...

journal_title：ACS medicinal chemistry letters

authors： Pugh KW,Zhang Z,Wang J,Xu X,Munthali V,Zuo A,Blagg BSJ

更新日期：2020-06-11 00:00:00

abstract：:Natural and synthetic histone deacetylase (HDAC) inhibitors generally derive their strong binding affinity and high potency from a key functional group that binds to the Zn(2+) ion within the enzyme active site. However, this feature is also thought to carry the potential liability of undesirable off-target interactio...

journal_title：ACS medicinal chemistry letters

authors： Vickers CJ,Olsen CA,Leman LJ,Ghadiri MR

更新日期：2012-04-26 00:00:00

abstract：:Minibodies show rapider blood clearance than IgGs due to smaller size that improves target-to-background ratio (TBR) in in vivo imaging. Additionally, the ability to activate an optical probe after binding to the target greatly improves the TBR. An optical imaging probe based on a minibody against prostate-specific me...

journal_title：ACS medicinal chemistry letters

authors： Watanabe R,Sato K,Hanaoka H,Harada T,Nakajima T,Kim I,Paik CH,Wu AM,Choyke PL,Kobayashi H

更新日期：2014-01-17 00:00:00

abstract：:Medicinal chemists have increasing opportunities to transition from the pharmaceutical industry to academic medical centers interested in translational research. This Viewpoint highlights some of the differences between these two cultures and strategies to succeed in academic drug discovery. ...

journal_title：ACS medicinal chemistry letters

authors： Barrow JC

更新日期：2019-04-15 00:00:00

abstract：:The polyether ionophore salinomycin has recently gained attention due to its exceptional ability to selectively reduce the proportion of cancer stem cells within a number of cancer cell lines. Efficient single step strategies for the preparation of hydroxamic acid hybrids of this compound varying in N- and O-alkylatio...

journal_title：ACS medicinal chemistry letters

authors： Borgström B,Huang X,Chygorin E,Oredsson S,Strand D

更新日期：2016-04-25 00:00:00

abstract：:A number of biologically active nucleoside analogues contain the adenine isostere 4-amino-pyrrolo[2,1-f][1,2,4]triazine connected to various sugar moieties through a C-C anomeric linkage. We employed palladium-catalyzed cross-coupling chemistry to promptly functionalize the 7-position of such a heterocyclic scaffold w...

journal_title：ACS medicinal chemistry letters

authors： Li Q,Groaz E,Persoons L,Daelemans D,Herdewijn P

更新日期：2020-07-09 00:00:00

abstract：:Insulin-regulated aminopeptidase (IRAP) is a transmembrane zinc metallopeptidase with many important biological functions and an emerging pharmacological target. Although previous structural studies have given insight on how IRAP recognizes linear peptides, how it recognizes its physiological cyclic ligands remains el...

journal_title：ACS medicinal chemistry letters

authors： Mpakali A,Saridakis E,Giastas P,Maben Z,Stern LJ,Larhed M,Hallberg M,Stratikos E

更新日期：2020-06-02 00:00:00

abstract：:Modifications at the basic nitrogen of the benzomorphan scaffold allowed the development of compounds able to segregate physiological responses downstream of the receptor signaling, opening new possibilities in opioid drug development. Alkylation of the phenyl ring in the N-substituent of the MOR-agonist/DOR-antagonis...

journal_title：ACS medicinal chemistry letters

authors： Pasquinucci L,Parenti C,Ruiz-Cantero MC,Georgoussi Z,Pallaki P,Cobos EJ,Amata E,Marrazzo A,Prezzavento O,Arena E,Dichiara M,Salerno L,Turnaturi R

更新日期：2020-01-28 00:00:00

abstract：:B-cell lymphoma 6 (BCL6) is a transcriptional repressor frequently deregulated in lymphoid malignancies. BCL6 engages with number of corepressors, and these protein-protein interactions are being explored as a strategy for drug development. Here, we report the development of an irreversible BCL6 inhibitor TMX-2164 tha...

journal_title：ACS medicinal chemistry letters

authors： Teng M,Ficarro SB,Yoon H,Che J,Zhou J,Fischer ES,Marto JA,Zhang T,Gray NS

更新日期：2020-04-03 00:00:00

abstract：:Substitution of rigidified A3 adenosine receptor (AR) agonists with a 2-((5-chlorothiophen-2-yl)ethynyl) or a 2-(4-(5-chlorothiophen-2-yl)-1H-1,2,3-triazol-1-yl) group provides prolonged protection in a model of chronic neuropathic pain. These agonists contain a bicyclo[3.1.0]hexane ((N)-methanocarba) ring system in p...

journal_title：ACS medicinal chemistry letters

authors： Tosh DK,Crane S,Chen Z,Paoletta S,Gao ZG,Gizewski E,Auchampach JA,Salvemini D,Jacobson KA

更新日期：2015-05-20 00:00:00

abstract：:A novel series of alkoxyimino derivatives as S1P1 agonists were discovered through de novo design using FTY720 as the chemical starting point. Extensive structure-activity relationship studies led to the discovery of (E)-1-(4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2-ethylbenzyl)azetidine-3-carbo...

journal_title：ACS medicinal chemistry letters

authors： Pan S,Gray NS,Gao W,Mi Y,Fan Y,Wang X,Tuntland T,Che J,Lefebvre S,Chen Y,Chu A,Hinterding K,Gardin A,End P,Heining P,Bruns C,Cooke NG,Nuesslein-Hildesheim B

更新日期：2013-01-04 00:00:00

abstract：:Despite several years of research, only a handful of β-secretase (BACE) 1 inhibitors have entered clinical trials as potential therapeutics against Alzheimer's disease. The intrinsic basic nature of low molecular weight, amidine-containing BACE 1 inhibitors makes them far from optimal as central nervous system drugs. ...

journal_title：ACS medicinal chemistry letters

authors： Oehlrich D,Peschiulli A,Tresadern G,Van Gool M,Vega JA,De Lucas AI,Alonso de Diego SA,Prokopcova H,Austin N,Van Brandt S,Surkyn M,De Cleyn M,Vos A,Rombouts FJR,Macdonald G,Moechars D,Gijsen HJM,Trabanco AA

更新日期：2019-07-02 00:00:00