aromaticproteinspectralregions

theseproton

Anothersourceof minordifferencesinepitopemapsisthesolven

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

100%D2O

SaturationtransferNMRwasapioneeringtechniquedevelopedin1979

wereobtainedbycollecting128scans

nfact,thereisanincreaseofsensitivitywiththesizeofproteinduetoamoreefficientinter-andintramolecularsaturationtransfer

Usinghigherfieldspectrometerswillmakethemethodevenmoreefficientsincesensitivityandspindiffusionincreasewithfieldstrength

wheatgermagglutinin

thedegreeofsaturationofligandsdependsonthesizeoftheprotein,theoffset,andthedurationoftheon-resonanceirradiation,thedissociationrateconstantkoff,andtheexcessofligand

highturnoverratesresultinalargereffectathigherligand-to-proteinratios.SlowdissociationrateswillyieldsmallerSTDNMRsignalsand,thus,reducesensitivity

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

excess concentration of ligand

Off‐ratescreening

Thermalmeltmethodsunreliable

nn8

Substitution Count [Query]

restrictingligandconformationalflexibilityacceleratedthebinding

seriesofagonistsoftheA2Aadenosinereceptor

narrowpassageway

diffusion-limitedon-rate(kon109M1s1)

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

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

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

GAUSSIAN09

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

(i) consistent with that obtained from REMD simulations

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

PD3.1)

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

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

Timings for Open3DALIGN validation suites

(0.02 s conformation-1)

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

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

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

AR Recruits SRC-3 and p300 Mainly through Its NTD

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)

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

in the presence of 1mM R1881

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

both NTDs also connect toeach other to contribute to AR dimerization

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

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

astigmatism

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

a predominant helical filament type in all three case

FROG2

nscm

Low-MODe (LMOD) optimization methods

LMOD

parm

strip

Coordinates (COORDS) Data Set Commands

cluster

cluster

nscm

ntwr

ntt

tempi

temp0

ntr

ntc

taup

igb

ig

irest

imin

rms | rmsd

Atom Mask Selection Syntax

icrosecond time scale molecular dynamics

Solvent-balance method of computing binding enthalpies.

11

KI-MS2-002

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

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

the PanDDA approachincreased the hit yield significantl

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

FragMAXapp

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

All of the fragment hits in this case were identified through visual inspection of the electron density maps

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

crystallography has become the most popular technique for FBLD

cryoprotectant

1,103-membered F2X-Universal Library

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

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

00 μmol/L of the compound mixture

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

Chemdiv and Enamine,

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

emphasizing X-ray crystallography.

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

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,

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

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

use ligand-observed NMR

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

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

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

cryoprotectant

but subsequent trials failed to show any acti

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

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

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

chloroform extracts of ten marine sponges werescreened for their antimicrobial activit

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

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

Dynamic properties of PPAR-γ

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

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

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

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

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)

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

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

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

. 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

6TX6, 6TX4, 6TX7, 6TX8, 6TX5 and 6TX9). (

ragment 1

site-identification by ligand competitive saturation (SILCS)

MiniFrags

IkBaphosphopeptide (IPP)

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

10.2 inclusive

ecommended choice isgaff2

gamma_ln

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

ff19SB

wt1mg_min_water

ecommended choice isgaff2

nrt1 deletion

DPI

ramifications

Protein:lipid~3:1

sapiens

Over 60 Drug Discovery Webinars

4 missing angle parameters

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

parmchk

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

GAFF

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

ositionalCartesian restraint

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

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.

SARS-CoV PLpro

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

Arv7

AutoDock Vina ignores the user-supplied partial charges

available

theMMFFMolProperties

MMFFGetMoleculeForceField(),

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;

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

Structure-Based Design

6NTS

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

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.

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

Poised

with accordingly increased sensitivity

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

ZDD (ZINC drug database) containing 2924

Natural products database

Boronoethyl

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.

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

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

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

N612 of GluN2B

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

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

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

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

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

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.

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

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)

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

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

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

myc-TEAD1

cking pose for compound 3.1.

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

INC)

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

YAP peptide