263 Matching Annotations
  1. Last 7 days
    1. aromaticproteinspectralregions

      if compound contains aryl ring, then we should not use this frequency to saturate the system

    2. theseproton

      proton of polar residues

    3. Anothersourceof minordifferencesinepitopemapsisthesolven

      Hydrogen atoms of polar residues will be exchanged to Deuterium when solvent is D2O. In contrast, they will not excha

    4. incethefrequenciesof irradiationcan be chosen,we can selectwhattypesof proteinprotonswill be “directlyirradiated”,so thatthe differenceswill highlightpartsof the ligandcontactingthosetypesof proteinresiduesin the boundstate

      different irradiation frequency will highlight different parts of the types of protein residues that contact with ligand.


    1. 100%D2O

      100% D2O is needed, to allow sufficient STD to ligand and not water or other solvent.

    2. SaturationtransferNMRwasapioneeringtechniquedevelopedin1979

      STD was used first in 1979


    1. wereobtainedbycollecting128scans

      number of scans can be accumulated?

    2. nfact,thereisanincreaseofsensitivitywiththesizeofproteinduetoamoreefficientinter-andintramolecularsaturationtransfer

      larger size of protein will increase the sensitivity due to more efficient inter- and intramolecular saturation transfer

    3. Usinghigherfieldspectrometerswillmakethemethodevenmoreefficientsincesensitivityandspindiffusionincreasewithfieldstrength

      higher field strength will help increase the sensitivity

    4. wheatgermagglutinin
    5. thedegreeofsaturationofligandsdependsonthesizeoftheprotein,theoffset,andthedurationoftheon-resonanceirradiation,thedissociationrateconstantkoff,andtheexcessofligand

      the degree of saturation of ligands depends on the size of the protein, the offset, and the duration of the on-resonance irradiation, the dissociation rate constant koff, and the excess of ligand

    6. highturnoverratesresultinalargereffectathigherligand-to-proteinratios.SlowdissociationrateswillyieldsmallerSTDNMRsignalsand,thus,reducesensitivity

      Slow dissociation rates will yield smaller STD NMR signals and, thus, reduce sensitivity



    1. NMR STD experiment

    2. The on-resonance frequency needs to be optimized for each protein

      How to optimize it? How to measure if the frequency is good enough?

    3. excess concentration of ligand

      EL hereafter

    1. nn8

      number of entries on line

    2. Substitution Count [Query]

      substitution count


  2. Jul 2020
    1. restrictingligandconformationalflexibilityacceleratedthebinding

      conformation is related to kon

    2. seriesofagonistsoftheA2Aadenosinereceptor

      really? I need to check the original data.

    3. narrowpassageway

      How to define is a passageway is narrow or not?

    4. diffusion-limitedon-rate(kon109M1s1)

      this should be the maximum kon, right?



    1. the key method for conformation comparison used in this artical is wrong, so the result is not very informative.

    2. As shown in Appendix B, for the specific case of AMP, we could have reducedthe computational cost grossly by one order of magnitude

      100 us is enough?

    3. For the purpose of comparing the features of the conformational ensemble extracted from ourMD simulations (plain and replica-exchange) to the structures generated by conformer generators(vide infra), we performed a symmetric root mean square displacement-based cluster analysis using thehierarchical agglomerative algorithm

      clustering is used to compare conformations

    4. AMBERTOOLS14[59] adopting GAFFparameters [42] for the molecule and the TIP3P model of water

      GAFF for LMW, TIP3P water

    5. GAUSSIAN09

      commercial QM tool

    6. performs slightly better than some widely-used conformer generation tools when considering boththe abilities to generate high-diversity conformational ensembles and to reproduce experimentally theavailable structures

      plain MD sampled slightly better diverse conformational space than conformer generation tools

    7. (i) consistent with that obtained from REMD simulations

      plain MD sampled similar conformational space as REMD How they measured?

    8. there is a negligible impact of these differences on zwitterionicAMP dynamics as sampled alongμs-long MD simulations using both sets of charges

      charges did not show significant difference for MD



    1. PD3.1)

      How did they find it? 1st round: They did VS against ZINC8 using 3kys as protein model, and selected top 100000 2nd round: The did VS using 5 representative MD snapshots of 3kys, and selected 1000 hits

    2. The selection process from 1000 (seeSupplement Data File S1) to thefinal list of 16 compounds

      3rd VS: visual inspection and property filter

    3. he enrichment process from thefirst BUDEdocking reduced the number of conformers from 160 millionto 100 000

      1st VS: 100000 hits


    1. Timings for Open3DALIGN validation suites

      speed is provided. thanks to the author

    2. (0.02 s conformation-1)

      2 seconds for 100 alignment.

    3. themixed and atom-based superposition algorithms are thosegiving rise to the most consistent and well-ordered align-ments,

      atom-based and mixed algorithms are recommended.



    1. 0.6mgof recombinant AR, SRC-3 and p300 proteins were incubated with 200 ng of ARE DNA in the presence of 1mM R1881

      the SRC-3 and p300 should be full length protein

    2. AR interacts with SRC-3 through its N-terminal domain (NTD)

      this is contradictory with previous observation that LBD binds with SRC3. https://www.jbc.org/content/early/2010/01/19/jbc.M109.085779.full.pdf?with-ds=yes However, previous result are based on only the truncated AR with SRC3 peptide, which is far from the native state of full length AR and SRC. So I trust the current finding.

    3. AR Recruits SRC-3 and p300 Mainly through Its NTD

      this is contradictory with previous observation that LBD binds with SRC3. https://www.jbc.org/content/early/2010/01/19/jbc.M109.085779.full.pdf?with-ds=yes However, previous result are based on only the truncated AR with SRC3 peptide, which is far from the native state of full length AR and SRC. So I trust the current finding.

    4. Preclinical studies of a p300 inhib-itor also reveal efficacy in patient-derived prostate tumor ex-plants (Butler et al., 2019) and the growth of castration-resistantprostate cancer (Jin et al., 2017)


      would p300 inhibitor be more effective to prostate cancer than AR inhibitor? would p300 inhibitor have more off-target issues?

    5. this is a Cryo-EM paper. It demonstrated how scientist map proteins to the volume data from EM. The author combined result from antibody labelling, protein docking, pull down and CoIP to map the protein to the volume data.

    6. The rela-tively large-sized AR NTDs, however, wrap around the LBDs,blocking the access of SRC-3 to the LBD. Consequently,SRC-3 is solely recruited by the AR NTD, and p300 recruitmentis stabilized by contacting two AR NTDs

      AR NTD wrap around its LBD. Does AR NTD mimic the function of some NR co-activator? These conclusion is only true when AR agonist R1881 is added, check figure 4

    7. in the presence of 1mM R1881

      does AR NTD interact with SRC-3 without R1881?

    8. Based on the structure (Figure 3C), we did not observe thatSRC-3 directly contacts the AR LBDs. The interaction betweenSRC-3 and the AR NTD is clearly observed in our structuraldata

      SRC3 interacts with NTD, but not LBD as revealed by the structure

    9. both NTDs also connect toeach other to contribute to AR dimerization

      NTD forms PPI too

    10. The combination of the anti-body locations, crystal structure docking, and the observed DNA

      docking, antibody labelling and DNA position allows the modeling building



    1. different conformation of the β-helix region creates a hydrophobic cavity that is absent in tau filaments from the brains of patients with Alzheimer’s disease

      this cavity is a mystery revealed by this article. the authors believe it is a hydrophobic cavity. Actually, at similar position of the Alzheimer's tau filament, a smaller tunnel exists. beta-helix may mean a helical ultrastructure formed by beta sheet.

    2. astigmatism


    3. additional density—which is not present in the Alzheimer fold—is surrounded by the density of the tau protein chain within the ordered cor

      unrevealed density

    4. a predominant helical filament type in all three case

      helical filament is an assembly of tau protein


    1. FROG2

      it did not update since 2010.


    1. nscm

      nscm definition

    2. Low-MODe (LMOD) optimization methods

      Could this be used to LMW?

    3. LMOD

      could I use this for conformational search

    4. parm

      multiple topology files

    5. strip


    6. Coordinates (COORDS) Data Set Commands

      modify the trajectory immediately

    7. cluster


    8. cluster

      cluster the trajectory

    9. nscm

      nscm=0 by default, and 0 means no change is made to recenter the system This is used in Dan's WatMD production run, maybe because he put position restraints to the sytem, so he does not want Amber to recenter the system. http://archive.ambermd.org/200704/0199.html

    10. ntwr


    11. ntt


    12. tempi


    13. temp0


    14. ntr


    15. ntc


    16. taup


    17. igb


    18. ig


    19. irest


    20. imin


    21. rms | rmsd


    22. Atom Mask Selection Syntax

      selection syntax



    1. icrosecond time scale molecular dynamics

      us scale MD

    2. How to deal with solute concentration in MD simulation?

    3. Solvent-balance method of computing binding enthalpies.

      the total potential energy of each system is used ?



    1. 11

      this paper may contain a dataset of kinetics


    1. The F2X-Entry Screen is a subset of the F2X-Universal Library

      F2X entry is a subset of F2X universal

    2. However, for compound libraries witheven smaller compounds (about five to seven non-hydrogenatoms) higher hit rates were reported

      the smaller the fragment, the higher the hit rate. the purpose of different fragment libraries are different, both want to identify hot spots, and Reilly wanted to help MedChem optimization

    3. the PanDDA approachincreased the hit yield significantl

      PanDDA method seems good

    4. Of these, 10 hits (10 binding events) were observed onAar2, 11 hits (12 binding events) on RNaseH, and 1 hit (one bind-ing event) at the functional interface of the two proteins

      exciting results, 3 binding sites were identified with ligand

    5. FragMAXapp

      https://www.maxiv.lu.se/industry/ it is a synchrotron facility

    6. numerous commercial libraries are availableon the market, a large subset of them being reviewed in detail

      need to read this paper


  3. Jun 2020
    1. All of the fragment hits in this case were identified through visual inspection of the electron density maps

      manual inspection of the density map to find the binder

    2. Soaking each of the compounds at 100 mM yielded 8 structures, 5 of which bound in the active site.

      100mM soaking of each compound

    3. crystallography has become the most popular technique for FBLD

      FBDD by crystallography is most popular from 2019

    4. cryoprotectant


    1. 1,103-membered F2X-Universal Library

      what compounds are contained in the library?

    2. ry presentation of the libraries al-lows CFS campaigns to be carried out with or without the co-solvent DMSO present.

      what does "dry presentation" mean?



    1. 200 μmol/L potential hit compound or 200 μmol/L potential hit compound in the presence of 5 μmol/L protein.

      working solution of single compound NMR: 200 uM compound, 5 uM protein

    2. 00 μmol/L of the compound mixture

      working solution of mixture NMR: 200 uM compound, 20 uM protein

    3. DMSO-d6 stock solu-tions with a group compound concentration of 10 mmol/L were prepared and used for screening

      stock solution: 10 mM = sum of conc. of all group member?

    4. Chemdiv and Enamine,



    1. During the fragment hit-to-lead process, we typically synthesize 50–100 compounds to increase the binding affinity from millimolar to nanomolar, and we routinely generate multiple lead series for each target

      50-100 compounds from millimolar to nanomolar, that is too successful, 10^6 increase

    2. emphasizing X-ray crystallography.

      emphasizing X-ray is Astex's way

    3. the most potent fragment is often not the best starting point for hit-to-lead chemistry.

      a good lession: the most potent hit may not be the best starting point for further optimization.

    4. Although better cross-validation would provide increased confidence in fragment hits, there is a danger that this may also result in the systematic selection of more potent hits,

      this is a dilemma, if you expect a hit to be validated in both NMR and X-ray, you are actually expect a stronger binder.

    5. great importance should be placed on accurately characterizing the solubility of a fragment library

      for X-ray screening, solubility must be good enough. what is the cutoff?

    6. observe a correlation of 30–40% using these two techniques.

      only 30~40% correlation between X-ray and ligand observed NMR

    7. use ligand-observed NMR

      Does "ligand observed NMR" equal to "ligand 1D-NMR"

    8. Another area of active debate centres on the lack of correlation of fragment hits obtained using different detection techniques

      I have not notice this before, which reflects my lack of FBDD experiences.

    9. that current fragment libraries are largely composed of ‘flat structures’

      flat structures are not good enough for some protein targest?

    10. our results support the view that less complex molecules give a higher hit rat

      FBDD is good for hit identification



    1. TIGIT small molecule allosteric inhibitor

    2. but subsequent trials failed to show any acti

      cellular activity is not promising

    1. UT-34 induced the regression of enzalutamide-resistant tumors at doses when the AR is degraded

      What dose?

    2. T-34 caused the degradation of the full-length AR, but not the tau-5-deleted AR

      tau-5 locates between AF-1 and DBD, deletion of this region may cause significant protein structure change, such change may result in different AR degradation profile which is irrelavant with UT-34

    1. SDS-PAGE disrupts noncovalent interactions and is used to determine covalent binding.

      SDS-PAGE is used to identify covalent binder with the help of click chemistry



    1. chloroform extracts of ten marine sponges werescreened for their antimicrobial activit

      chloroform extracts were directly used without further separation for antimicrobial activity test. How to separate the active indigrient then?

    2. more than5000 different compounds have been isolated fromabout 500 species of sponges

      will this reference provide a list of extracts of marine sponges

    3. Since then well over 14,000 dif-ferent natural products from marine organismshave been described

      will this reference provide a list of extracts of marine sponges



    1. Our laboratory recently reported the structure of the intact PPARγ-RXRα heterodimer bound to its idealized DNA site, with coactivator peptides and ligands of both receptors

      the author of this review published the full length structure of PPARg

    1. he studies using the LNCaP xenograft tumor model show that JJ-450 can suppress AR functionin vivo

      in vivo activity

    2. inhibiting both full-length AR andAR splice variants lacking LBD.

      inhibit both FL and ARv7

    3. with ()-JJ-450 beingapproximately 9-fold more potent than (þ)-JJ-450 in the luciferasePSA-reporter assay (24)

      chirality is important for the activity



    1. Enzalutamide is an inhibitor of androgen-receptor signaling that exerts its activity by binding avidly to the ligand-binding domain of the androgen receptor, competing with and displacing the natural ligands of this receptor (testosterone and dihydrotestosterone)

      Enzalutamide binds to AR LBD

    1. A 2 fold molar excess of peptide was added to the protein prior to crystallization (RGAFQNLFQSV).

      why such a peptide is added for AR crystal structure?



    1. he discoveryof five distinct pockets in these complexes expands the possibilities fortargeting HIF protein activities with drug-like molecules for thera-peutic purposes.

      5 distinct pocket proposed in this paper

    2. A proposed mechanism by which 0X3 binding candestabilize the HIF-2a–ARNT heterodimer.

      R366 conformation is almost identical in apo and X03 bound structures(4zp4 vs 4zqd)


    1. . This mech-anistic hypothesis suggests perturbation of a few amino acidresidues within the PAS-B domain is sufficient to disrupt a largeprotein:protein interface leading to complete blockage of HIF2a-driven gene transcription

      in fact, the PPI is not disrupted, but altered.


  4. May 2020
    1. 6TX6, 6TX4, 6TX7, 6TX8, 6TX5 and 6TX9). (

      crystal structures solved in this paper

    2. ragment 1

      if fragment 1 is too acidic, then fragment 3 and 7 are too basic. And fragment 3 and 7 are not validated as binder

    3. this paper may related to the previous one of Daniel Seeliger. FBDD is not only useful for hit fidning, but also for MoA exploration. CADD is particular suitable for FBDD as the sampling of small molecule will more thourough

    4. site-identification by ligand competitive saturation (SILCS)


    5. MiniFrags

      crystallograpy method for hit finding



    1. IkBaphosphopeptide (IPP)

      peptide binder to beta-TRCP


    1. when using miniconda, you can’t move the Amber install folder fromits original location

      do not move amber install folder in bundled Miniconda is chosen during installation

    2. 10.2 inclusive

      CUDA10.2 is supported

    3. ecommended choice isgaff2

      gaff2 is recommended for organic molecule

    4. gamma_ln

      collision frequency, in ps-1

    5. OPCwater model in combination with the ff99SB was found to improve, significantly, accuracy of atomistic simulationsof IDPs

      Myc is a typical IDP. To model Myc, force field must be carefully chosen.

    6. ff19SB


    1. ecommended choice isgaff2

      gaff2 is recommended for organic compounds



    1. nrt1 deletion

      highlights one transporter thatdisplays a significant extent of such resistance (as thenrt1dele-tant).NRT1encodes a nicotinamide riboside transporter, whichled us to hypothesize (i) that such a deletant would display resis-tance to DPI when cultured axenically, and (ii) that nicotinic acidwould be able to compete with the DPI and effect phenotypicresistance.Figure 2Bshows that both predictions are entirelyfulfilled

    2. DPI

      Diphenylene iodonium

    3. ramifications


    4. Protein:lipid~3:1

      this ratio is contrary to the quote 1:10 Lipitor get through the membrane through OATP1B1?

    5. sapiens

      Human cell has the most number of carriers

    6. Over 60 Drug Discovery Webinars



    1. 4 missing angle parameters

      no missing angle parameters when processed in Amber18

    2. Ideally you should really test these parameters (by comparing to ab initio calculations for example) to ensure they are reasonable

      How to compare?

    3. parmchk

      parmchk2 in Amber18

    4. C, N, O, S, P, H, F, Cl, Br and I

      GAFF only supports 10 elements?

    5. GAFF


    1. the commented Python scripts optFromSmiles.py, optLigandInProtein.py and torsionalScan.py which serve as examplesof simple and constrained MMFF minimizations

      I will learn these scripts

    2. ositionalCartesian restraint

      Cartesian restraints are available in Schrodinger MacroModel, how to implement them? some example scripts are included in Additional file 1 of this article

    3. The possibility of adding these restrainingpotentials to the force field expression has also beenadded to the existing RDKit UFF implementation

      Rdkit UFF also support cartesian restraints

    4. relax ligand-receptor complexeswithout causing major alterations of their originalgeometry, or to perform a torsional scan on a selecteddihedral while relaxing the rest of the molecule.

      such functions are like Schrodinger MacroModel, how to implement them?



    1. MONN contains a pairwise interaction prediction module, which can capture the non-covalent interactions between atoms of a compound and residues of a protein with extra supervision from the labels extracted from available high-quality 3D compound-protein complex structures

      does that mean MONN can predict binding site

    2. this is done by Tshinghua Univ

  5. Apr 2020
    1. AutoDock Vina ignores the user-supplied partial charges

      partial charge is ignored because the scoring function treated electrostatic interactions with other parameters.

    1. theMMFFMolProperties

      assign atom type and charge

    2. MMFFGetMoleculeForceField(),

      this is also an important step



    1. Is UFF a all atom force field?



    1. Mixed the plate thoroughly and incubated for one hour at room temperature. Then 5 μL development solution was added to each well and the plate was incubated for 1h at room temperature;

      the compound and kinase are incubated together for at least 2 hours. And 2 hours is enough for covalent adduct to form. if compound can form covalent adduct with FGFR1, why FGFR1 inhibition IC50 is so poor?

    1. over 40 specificity-determining regulatory ‘‘B’’subunits

      subunit B is a variable unit

    2. Structure-Based Design

      which structure they used?

    3. 6NTS

      PDB code, but it is not available in PDB website yet



    1. e submit that the use of a crystallographic primary screenfollowed by rapid poised chemistry to generate a follow-uplibrary offers a new, powerful method in hit discovery and leadseries selectio

      method summary: crystallography as primary screen, followd by rapid poised chemistry

    2. he ten reactions were selected to create poisedscaffolds with which to perform substructure searches. Thepoised fragment chemical space was further augmented withtwelve heterocycle forming reactions as dened by Hartenfelleret al.33and an oxazole formation developed in our own lab.

      poised fragment are generated by matching 10 reaction from 2011 ref, 12 heterocycle forming reaction from Hartenfeller ref, and 1 oxazole formation reaction

    3. As a simpleexample, an amide bond can be deconstructed into an acidchloride and an amine.

      example of poised bond

    4. Poised


    5. with accordingly increased sensitivity

      higher concentration of compounds increased the sensitivity of crystallography, compared to solution screen.

    6. A poised fragment library enables rapid syntheticexpansion yielding thefirst reported inhibitors ofPHIP(2), an atypical bromodomain

      what is the library? compound in the library can be expanded quickly by synthesis why they designed it this way? they did not find convincing hits from solution screen. They use crystallography as primary screening tech what assay they used for the screening? AlphaScreen competition assay as function assay



    1. Boronoethyl

      boron element



    1. S(+)‐ketamine affinity for the PCP site could be three times higher than that of R(−)‐ketamine 94, which confers to S(+)‐ketamine a strong analgesic and anesthetic effect, at least two times stronger compared to the racemic mixture 115.

      S isofom of ketamine has stronger binding to PCP site than R isoform

    2. NMDA (specifically activated by N‐methyl‐D‐aspartate) and non‐NMDA 89 (such as AMPA [alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid] and KA [kainate]) receptors

      name of NMDA, AMPA and KA

    1. e it forms stable hydrogen bonds with the two pore-loop asparagine residues N614 (GluN1) and N612

      interaction with the Asn is observed in MD simulation

    2. The omit electron density map showed only electron density for the β-carbon of N612;

      sidechain of N612 is disordered in the crystal structure

    3. N612 of GluN2B

      nitrogen is interacting with N612 of GluN2B, so a positive charge is important here.

    4. The side effects of MK-801, which are probably a result of its high affinity for and long dwell time on the receptor, preclude its clinical application

      MK-801 has side effect, and may related to its high affinity and long off rate.

    5. small molecules that target the TMD, including MK-801 (dizocilpine) and memantine,

      MK-801 and memantine are targeting the TMD of NMDA

    6. Neurodegenerative disorders, chronic pain, stroke and schizophrenia have all been attributed to the dysfunction of NMDA receptors

      disease link to many neuro diseases

    7. the binding site of the NMDA receptor blocker, MK-801.

      MK-801 is an ion channel blocker



    1. The extracellular region of the human ACE2 enzyme is com-posed of two domains.

      two domains: 1. zinc metallopeptidase domain(N terminal, residues 19-611) 2. C-terminus (residues 612-740)

    2. the N terminus- andzinc-containing subdomain I (red), com-posed of residues 19–102, 290–397, and417–430; and the C terminus-containingsubdomain II (blue), composed of residues103–289, 398–416, and 431–615.

      definition of the two subdomains

    3. The metallopeptidase domain of ACE2 can be further dividedinto two subdomains (I and II)

      zinc metallopeptidase domain(N terminal, residues 19-611) can be further divided into two subdomains(I and II), which form the two sides of a long and deep cleft.


    1. 100 nM MLN-4760did not interfere with immunoprecipitation of ACE2 by S1-Ig,nor did this inhibitor interfere with S-protein-mediated infec-tion (Figure 4B and C)

      hACE2 inhibitorm MLN-4760, does not interfere with immunoprecipitation of ACE2 by S1-Ig, nor did this inhibitor interfere with S-protein-mediated infection. So ACE2 inhibtor should not be a good way to interfere SARS infection



    1. WIN site inhibitors that–in light of our recentwork–could be repurposed for targeting MYC

      WIN site inhibitor could be repurposed for targeting MYC

    2. We do notknow how the WIN site tethers WDR5 to chromatin.

      how the WIN site tethers WDR5 to chromatin?

    3. t disrupting the MYC–WDR5 interaction has real anti-cancer potential




    1. myc-TEAD1

      what is myc-TEAD1

    2. cking pose for compound 3.1.

      With AutoDock and 3kys, I can not reproduce the docking pose provided by this paper

    3. CPD3.1 also significantly inhibitedTEAD-dependent NLUC secretion at 20μM with IC50=70μM(Figure 4C), without affecting cell viability

      CPD3.1 is a part of Compound 3, but shows better IC50

    4. INC)

      they did virtual screen against ZINC



    1. We did not use the YAP peptides containing residues in interface1 because it has been shown that interface 1 is dispensable forYAP binding

      this is strange, as the YAP interface 1 segment is a beta strand, which forms multiple Hbond with TEAD. So how could it be dispensable for TEAD binding?

    2. YAP peptide

      what is the sequence of the peptide? it might be the peptide 1 in Fig 1D, which shows the strongest binding to TEAD, ~ 200 nM. Peptide 1 contains just the alpha helix and omega loop, so it is possible that the FA binding will affect the beta strand part which is missing in peptide 1