Hello!
I am currently working on a computational protein-ligand design problem and due to the nature of our approach we have a set of described interactions between protein residues and certain functional groups. Those functional groups are fairly limited, mostly just ones that show up in protein side chains, such as carbonyls, carboxylic acids, thioethers, thiols, hydroxyls, amides, amines and some aromatic things.
In terms of ligand-binding, can other functional groups be approximated to have a similar interaction to the ones I listed? The main examples I was considering were,
ether -> thioether, ester -> carbonyl, sulfoxide -> carbonyl, thioketone -> carbonyl.
The alternative to the approximation would be to not consider the interaction too heavily and mostly treat it as mostly hydrophobic.
Any input would be much appreciated!
Does anyone know how to stop ChemDraw from automatically reversing text when I rotate the position of the text? For example ABC goes to CBA if it's positioned on the right vs left side of the attached atom.
Thank you!
A bit of a weird question, as I am stuck on an endocrinology topic of the Inisitol-triphosphate pathway but I am not sure what they are referring to when they describe the 7 domain transmembrane protein, if they refer to the G-protein as well?
But also confused as all the images and videos show that this type of receptors only binds ligands to the ends of the Amino end, and not sure if that is true or there are more binding sites on the outside or even inside of the cell
What did y’all say for the purpose of chill ... is it to induce or inhibit germination of seeds? Also what did u write for it chill and the other ligand was bound to their receptors
I'm attempting to use Schrodinger Suite in order to identify potential new ligands for my group's target proteins. My general workflow is the following:
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Import PDB file for the protein
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Use the Protein Prep Wizard to prepare the protein
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Use Glide to generate a docking receptor grid
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Create all my molecules and use the Ligand Preparation Wizard
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Run Glide's extra precision docking module
Unfortunately, the results that I've been getting are largely useless. The positive control molecules (that we've proven bind to the protein in our assays) don't always correlate to predicted docking activity, and worse, the negative control molecules (that we know don't bind) will occasionally score highly for binding. Moreover, some of the positive molecules that Schrodinger docks are oriented the wrong way entirely inside the binding site (we have identified several key residues and the parent ligand's orientation via XRay Crystallography)! Am I missing a step along the way? Are there any common pitfalls that I should look out for? Any hidden options that I should tweak or disable entirely?
One of my labmates has been saying that computational chemistry is pretty much worthless, and at this point I'm starting to feel the same way -- but I know that there are groups that have used computation successfully. So if you've got any suggestions, comment below. I'd desperately love to hear them.
Journal of the American Chemical SocietyDOI: 10.1021/jacs.1c01799
Yuan Zeng, Shana Havenridge, Mustafa Gharib, Ananya Baksi, K. L. Dimuthu M. Weerawardene, Anna Rosa Ziefuß, Christian Strelow, Christoph Rehbock, Alf Mews, Stephan Barcikowski, Manfred M. Kappes, Wolfgang J. Parak, Christine M. Aikens, and Indranath Chakraborty
https://ift.tt/3gJqrre
As part of my thesis I was asked to create a dataset that holds data for predicting binding between proteins and ligands. In the past I have worked with BindingDB. My supervisor said that perhaps I can find other databases holding similar data. If you know of such, I would greatly appreciate the input.
This is juicy as can be, I was looking through SEC filings to find who is actually shorting Ligand. Then I stumbled upon this:
https://www.sec.gov/news/press-release/2018-190
The most prominent shorter besides fucking Citron, is a guy named Greg Lemelson. He was sentenced for misleading investors and distributing false claims when he shorted Ligand but of course he couldn't take the L. He is back now with a vengeance and heavily heavily short.
Read this:
https://www.sec.gov/litigation/litreleases/2018/lr24267.htm
*The Securities and Exchange Commission charged a hedge fund adviser and his investment advisory firm with illegally profiting from a scheme to drive down the price of San Diego-based Ligand Pharmaceuticals Inc., reaping more than $1.3 million of gains for the adviser and the hedge fund.*
Get in, now!
I am trying to paramaterize an analog of glucose. When I use script cgenff_charmm2gmx.py downloaded from the MacKerell website to convert ParamChem CGenFF toppar stream file from CHARMM to GROMACS format.
I put in the command:
python cgenff_charmm2gmx_py3_nx1.py BGC_fix.mol2 BGC.str charmm36-feb2021.ff
And I get:
Usage: RESNAME drug.mol2 drug.str charmm36.ff
How to fix this in order to generate my itp file?
Metalloprotein properties can be tuned by changing the primary metal coordination sphere. Here amber stop codon suppression with engineered pyrrolysyl-tRNA synthetases was used to replace the proximal histidine in myoglobin with a range of new amino acids. In addition to tuning the heme redox potential over a >200 mV range, these noncanonical ligands modulate the protein's carbene transfer activity with ethyl diazoacetate.
Abstract
Changing the primary metal coordination sphere is a powerful strategy for tuning metalloprotein properties. Here we used amber stop codon suppression with engineered pyrrolysyl-tRNA synthetases, including two newly evolved enzymes, to replace the proximal histidine in myoglobin with Nδ-methylhistidine, 5-thiazoylalanine, 4-thiazoylalanine and 3-(3-thienyl)alanine. In addition to tuning the heme redox potential over a >200 mV range, these noncanonical ligands modulate the protein's carbene transfer activity with ethyl diazoacetate. Variants with increased reduction potential proved superior for cyclopropanation and N–H insertion, whereas variants with reduced Eo values gave higher S–H insertion activity. Given the functional importance of histidine in many enzymes, these genetically encoded analogues could be valuable tools for probing mechanism and enabling new chemistries.
https://ift.tt/3xcny9M
The transfer of an intact cyclo-E3 ligand (E=P, As) from the nickel complex [Cp′′′Ni(η3-E3)] to the anionic cobalt complex [Cp′′′Co(η3-E3)]− was achieved, which was afterwards quenched with main group electrophiles such as chlorophosphanes (R2PCl). That way, the E3 cycle can be expanded to a substituted four-membered ring, which undergoes further rearrangement processes by ring contractions to a cyclo-E3 ligand with an exocyclic {PR2} unit.
Abstract
A synthetic pathway for the synthesis of novel anionic sandwich complexes with a cyclo-E3 (E=P, As) ligand as an end deck was developed giving [Cp′′′Co(η3-E3)]− (Cp′′′=1,2,4-tri-tert-butylcyclopentadienyl, E=P ([5]), As ([6])) in good yields suitable for further reactivity studies. In the reaction with the chlorophosphanes R2PCl (R=Ph, Cy, tBu), neutral complexes with a disubstituted cyclo-E3P (E=P, As) ligand in [Cp′′′Co(η3-E3PR2)] (E=P (7 a–c), As (9 a–c)) were obtained. These compounds can be partially or completely converted into complexes with a cyclo-E3 (E=P, As) ligand with an exocyclic {PR2} unit in [Cp′′′Co(η2:η1-E3PR2)] (E=P (8 a–c), As (10 a–c)). Additionally, the insertion of the chlorosilylene [LSiCl] (L=(tBuN)2CPh) into the cyclo-E3 ligand of [5] and [6] was achieved and the novel heteroatomic complexes [Cp′′′Co(η3-E3SiL)] (E=P (11), As (12)) could be isolated. The reaction pathway was elucidated by DFT calculations.
https://ift.tt/3uBUQO0
A human 2-oxoglutarate and FeII dependent oxygenase was engineered to possess only one protein FeII binding ligand. The resultant variants retained significant levels of catalytic activity. Biomimetic catalysts containing only one metal binding site are therefore of interest.
Abstract
Aspartate/asparagine-β-hydroxylase (AspH) is a human 2-oxoglutarate (2OG) and FeII oxygenase that catalyses C3 hydroxylations of aspartate/asparagine residues of epidermal growth factor-like domains (EGFDs). Unusually, AspH employs two histidine residues to chelate FeII rather than the typical triad of two histidine and one glutamate/aspartate residue. We report kinetic, inhibition, and crystallographic studies concerning human AspH variants in which either of its FeII binding histidine residues are substituted for alanine. Both the H725A and, in particular, the H679A AspH variants retain substantial catalytic activity. Crystal structures clearly reveal metal-ligation by only a single protein histidine ligand. The results have implications for the functional assignment of 2OG oxygenases and for the design of non-protein biomimetic catalysts.
https://ift.tt/3gxvjRN
PdII-catalyzed β- or γ-C(sp3)–H carbonylation of free carboxylic acids, a new method for the synthesis of a wide range of cyclic anhydrides, is reported. Decarboxylative functionalization of the installed carboxyl group provides access to diverse β-functionalized aliphatic acids. The enantioselective C–H carbonylation of cyclopropanecarboxylic acids is also achieved.
Abstract
The development of C(sp3)–H functionalizations of free carboxylic acids has provided a wide range of versatile C−C and C−Y (Y=heteroatom) bond-forming reactions. Additionally, C–H functionalizations have lent themselves to the one-step preparation of a number of valuable synthetic motifs that are often difficult to prepare through conventional methods. Herein, we report a β- or γ-C(sp3)–H carbonylation of free carboxylic acids using Mo(CO)6 as a convenient solid CO source and enabled by a bidentate ligand, leading to convenient syntheses of cyclic anhydrides. Among these, the succinic anhydride products are versatile stepping stones for the mono-selective introduction of various functional groups at the β position of the parent acids by decarboxylative functionalizations, thus providing a divergent strategy to synthesize a myriad of carboxylic acids inaccessible by previous β-C–H activation reactions. The enantioselective carbonylation of free cyclopropanecarboxylic acids has also been achieved using a chiral bidentate thioether ligand
https://ift.tt/3y5UUHP
An unprecedented low-temperature, asymmetric Ni-catalyzed C−N cross-coupling of sterically hindered secondary amines with aryl chlorides via kinetic resolution is reported. A bulky yet flexible, chiral NHC ligand enables both low barrier oxidative addition and reductive elimination and high levels of enantiocontrol. Computational studies indicate that multiple σ-bond rotations of the C2-symmetric chiral NHC adapt to the changing needs of catalytic processes.
Abstract
The transition-metal-catalyzed C−N cross-coupling has revolutionized the construction of amines. Despite the innovations of multiple generations of ligands to modulate the reactivity of the metal center, ligands for the low-temperature enantioselective amination of aryl halides remain a coveted target of catalyst engineering. Designs that promote one elementary reaction often create bottlenecks at other steps. We here report an unprecedented low-temperature (as low as −50 °C), enantioselective Ni-catalyzed C−N cross-coupling of aryl chlorides with sterically hindered secondary amines via a kinetic resolution process (s factor up to >300). A bulky yet flexible chiral N-heterocyclic carbene (NHC) ligand is leveraged to drive both oxidative addition and reductive elimination with low barriers and control the enantioselectivity. Computational studies indicate that the rotations of multiple σ-bonds on the C2-symmetric chiral ligand adapt to the changing needs of catalytic processes. We expect this design would be widely applicable to diverse transition states to achieve other challenging metal-catalyzed asymmetric cross-coupling reactions.
https://ift.tt/3eymzrS
An end-on μ-1,2-peroxodicobalt(III) complex 1 involving a non-heme ligand system, L1, supported on a Sn6O6 stannoxane core has been found to be a reactive electrophile that is capable of initiating hydrogen atom and oxygen atom transfer reactions. The electrophilicity of 1 is attributed to the constraints provided by the Sn6O6 core and represents a new domain for metal−peroxo reactivity.
Abstract
μ-1,2-peroxo-bridged diiron(III) intermediates P are proposed as reactive intermediates in various biological oxidation reactions. In sMMO, P acts as an electrophile, and performs hydrogen atom and oxygen atom transfers to electron-rich substrates. In cyanobacterial ADO, however, P is postulated to react by nucleophilic attack on electrophilic carbon atoms. In biomimetic studies, the ability of μ-1,2-peroxo-bridged dimetal complexes of Fe, Co, Ni and Cu to act as nucleophiles that effect deformylation of aldehydes is documented. By performing reactivity and theoretical studies on an end-on μ-1,2-peroxodicobalt(III) complex 1 involving a non-heme ligand system, L1, supported on a Sn6O6 stannoxane core, we now show that a peroxo-bridged dimetal complex can also be a reactive electrophile. The observed electrophilic chemistry, which is induced by the constraints provided by the Sn6O6 core, represents a new domain for metal−peroxide reactivity.
https://ift.tt/3toUauo
I hear many different things, I was taught to pronounce it Lih-Gand but many people also say Lie-gand... so which one is it
So I recently asked this beautiful subreddit how to generate thermodynamic binding data, to which the replies were strongly satisfactory in pointing me in the right direction.
It looks relatively simple, and I have a number of the relevant receptors ready to plug in.
The issue is that the ligand I would like to analyze has only recently developed and the team responsible does not have a ligand file that I can use. Is it possible to create one, ideally with at least approximately accurate bond lengths/angles? What programs could I look into? Any directions you could point me in?
Journal of the American Chemical SocietyDOI: 10.1021/jacs.1c01843
Richard R. Thompson, Madeline E. Rotella, Xin Zhou, Frank R. Fronczek, Osvaldo Gutierrez, and Semin Lee
https://ift.tt/3cAQ8sO
The electron-rich cyanidometalates [Fe(CN)3]7− and [Ru(CN)3]7− represent the first examples of group 8 elements with an oxidation state of −IV. DFT calculations reveal a nominal d10s0 configuration, which corresponds to an effective charge of 2−. The high negative charge also weakens the C−N bonds by the population of antibonding states.
Abstract
Exceptionally electron-rich, nearly trigonal-planar tricyanidometalate anions [Fe(CN)3]7− and [Ru(CN)3]7− were stabilized in LiSr3[Fe(CN)3] and AE3.5[M(CN)3] (AE=Sr, Ba; M=Fe, Ru). They are the first examples of group 8 elements with the oxidation state of −IV. Microcrystalline powders were obtained by a solid-state route, single crystals from alkali metal flux. While LiSr3[Fe(CN)3] crystallizes in P63/m, the polar space group P63 with three-fold cell volume for AE3.5[M(CN)3] is confirmed by second harmonic generation. X-ray diffraction, IR and Raman spectroscopy reveal longer C−N distances (124–128 pm) and much lower stretching frequencies (1484–1634 cm−1) than in classical cyanidometalates. Weak C−N bonds in combination with strong M−C π-bonding is a scheme also known for carbonylmetalates. Instead of the formal notation [Fe−IV(CN−)3]7−, quantum chemical calculations reveal non-innocent intermediate-valent CN1.67− ligands and a closed-shell d10 configuration for Fe, that is, Fe2−.
https://ift.tt/3vDtR4G
Directed C-H functionalization has been realized as a complimentary technique to achieve borylation at a distal position of aliphatic amines. Here, we demonstrated the oxidative borylation at the distal delta position of aliphatic amines using various borylating agents, a palladium catalyst and a rightly tuned ligand in the presence of a cheap oxidant. Moreover, an organopalladium δ -C(sp 3 )-H activated intermediate has been isolated and crystallographically characterized to get mechanistic insight.
https://ift.tt/3pM5dwL
The oxidation of π-d conjugated coordination polymers (CCPs) accompanied with anion insertion has the merits of increasing the capacity and elevating the discharge voltages. However, the previous reports on this mechanism either required more investigations or showed low capacity and poor cyclablity. Herein, triphenylene catecholate-based two dimensional CCPs are constructed by employing inactive transition metal ions (Zn 2+ ) as nodes, forming Zn-HHTP. Substantial characterizations and theoretical calculations indicated the successive storage of cations and anions by redox of only ligands, leading to a high reversible capacity of ~150 mAh g -1 at 100 mA g -1 and remarkable capacity retention of 90% after 1000 cycles. On the contrary, as a control experiment, the analogue CCPs (Cu-HHTP) with Cu 2+ nodes, involved the redox of both ligands and metal ions and accompanied with the storage of only Na + -cations, showing much poorer cyclability. These results highlighted the importance of redox of only ligands for long-term cycle life and the insight into the storage mechanisms would deepen our understanding on CCPs for further design of CCPs with high performance.
https://ift.tt/3q6ZuBV
