Crystal Structure Of Ligand Research Articles

Preference of Small Molecules for Local Minimum Conformations when Binding to Proteins

It is well known that small molecules (ligands) do not necessarily adopt their lowest potential energy conformations when binding to proteins. Analyses of protein-bound ligand crystal structures have reportedly shown that many of them do not even adopt the conformations at local minima of their potential energy surfaces (local minimum conformations). The results of these analyses raise a concern regarding the validity of virtual screening methods that use ligands in local minimum conformations. Here we report a normal-mode-analysis (NMA) study of 100 crystal structures of protein-bound ligands. Our data show that the energy minimization of a ligand alone does not automatically stop at a local minimum conformation if the minimum of the potential energy surface is shallow, thus leading to the folding of the ligand. Furthermore, our data show that all 100 ligand conformations in their protein-bound ligand crystal structures are nearly identical to their local minimum conformations obtained from NMA-monitored energy minimization, suggesting that ligands prefer to adopt local minimum conformations when binding to proteins. These results both support virtual screening methods that use ligands in local minimum conformations and caution about possible adverse effect of excessive energy minimization when generating a database of ligand conformations for virtual screening.

Crystal Structure of Helicobacter pylori Formamidase AmiF Reveals a Cysteine-Glutamate-Lysine Catalytic Triad

Helicobacter pylori AmiF formamidase that hydrolyzes formamide to produce formic acid and ammonia belongs to a member of the nitrilase superfamily. The crystal structure of AmiF was solved to 1.75A resolution using single-wavelength anomalous dispersion methods. The structure consists of a homohexamer related by 3-fold symmetry in which each subunit has an alpha-beta-beta-alpha four-layer architecture characteristic of the nitrilase superfamily. One exterior alpha layer faces the solvent, whereas the other one associates with that of the neighbor subunit, forming a tight alpha-beta-beta-alpha-alpha-beta-beta-alpha dimer. The apo and liganded crystal structures of an inactive mutant C166S were also determined to 2.50 and 2.30 A, respectively. These structures reveal a small formamide-binding pocket that includes Cys(166), Glu(60), and Lys(133) catalytic residues, in which Cys(166) acts as a nucleophile. Analysis of the liganded AmiF and N-carbamoyl d-amino acid amidohydrolase binding pockets reveals a common Cys-Glu-Lys triad, another conserved glutamate, and different subsets of ligand-binding residues. Molecular dynamic simulations show that the conserved triad has minimal fluctuations, catalyzing the hydrolysis of a specific nitrile or amide in the nitrilase superfamily efficiently.

The use of biophysical methods increases success in obtaining liganded crystal structures

In attempts to determine the crystal structure of small molecule-protein complexes, a common frustration is the absence of ligand binding once the protein structure has been solved. While the first structure, even with no ligand bound (apo), can be a cause for celebration, the solution of dozens of apo structures can give an unwanted sense of déjà vu. Much time and material is wasted on unsuccessful experiments, which can have a serious impact on productivity and morale. There are many reasons for the lack of observed binding in crystals and this paper highlights some of these. Biophysical methods may be used to confirm and optimize solution conditions to increase the success rate of crystallizing protein-ligand complexes. As there are an overwhelming number of biophysical methods available, some of the factors that need to be considered when choosing the most appropriate technique for a given system are discussed. Finally, a few illustrative examples where biophysical methods have proven helpful in real systems are given.

Novel, Customizable Scoring Functions, Parameterized Using N-PLS, for Structure-Based Drug Discovery

The ability to accurately predict biological affinity on the basis of in silico docking to a protein target remains a challenging goal in the CADD arena. Typically, "standard" scoring functions have been employed that use the calculated docking result and a set of empirical parameters to calculate a predicted binding affinity. To improve on this, we are exploring novel strategies for rapidly developing and tuning "customized" scoring functions tailored to a specific need. In the present work, three such customized scoring functions were developed using a set of 129 high-resolution protein-ligand crystal structures with measured Ki values. The functions were parametrized using N-PLS (N-way partial least squares), a multivariate technique well-known in the 3D quantitative structure-activity relationship field. A modest correlation between observed and calculated pKi values using a standard scoring function (r2 = 0.5) could be improved to 0.8 when a customized scoring function was applied. To mimic a more realistic scenario, a second scoring function was developed, not based on crystal structures but exclusively on several binding poses generated with the Flo+ docking program. Finally, a validation study was conducted by generating a third scoring function with 99 randomly selected complexes from the 129 as a training set and predicting pKi values for a test set that comprised the remaining 30 complexes. Training and test set r2 values were 0.77 and 0.78, respectively. These results indicate that, even without direct structural information, predictive customized scoring functions can be developed using N-PLS, and this approach holds significant potential as a general procedure for predicting binding affinity on the basis of in silico docking.

Synthesis, crystal structures and multinuclear NMR spectroscopy of copper(I) complexes with benzophenone thiosemicarbazone

Reactions of benzophenone thiosemicarbazone (Hbztsc, Ph 2C N-NH-C( S)-NH 2) with copper(I) chloride/bromide in the presence of two moles of PPh 3, formed monomeric tetrahedral complexes, [CuX (η 1-S-Hbztsc)(PPh 3) 2] · CH 3CN (X = Cl, 1; Br, 2). It did not form similar complex with copper(I) iodide; rather it formed a trigonal planar complex [CuI(η 1-S-Hbztsc) 2] ( 3) with two moles of Hbztsc in absence of PPh 3. All the complexes have been characterized with the help of elemental analyses, IR, 1H, 13C, and 31P NMR spectroscopy, and single crystal X-ray crystallography. The crystal structure of ligand is also described. In all the complexes, benzophenone thiosemicarbazone is acting as a neutral S donor ligand in η 1-S bonding mode. NMR data support that the complexes remain stable in solution phase.

Design, synthesis and X-ray structure of protein-ligand complexes: important insight into selectivity of memapsin 2 (beta-secretase) inhibitors.

Structure-based design, synthesis, and X-ray structure of protein-ligand complexes of memapsin 2 are described. The inhibitors are designed specifically to interact with S2- and S3-active site residues to provide selectivity over memapsin 1 and cathepsin D. Inhibitor 6 has exhibited exceedingly potent inhibitory activity against memapsin 2 and selectivity over memapsin 1 (>3800-fold) and cathepsin D (>2500-fold). A protein-ligand crystal structure revealed cooperative interactions in the S2- and S3-active sites of memapsin 2. These interactions may serve as an important guide to design selectivity over memapsin 1 and cathepsin D.

Novel Cyclometallated Complexes Derived From a Halogenated Thiosemicarbazone. Crystal and Molecular Structures of 2-FC6H4C(Me)=NN(H)C(=S)NHPh and [(Pd{2-FC6H3C(Me)=NN=C(S)NHPh})2(μ-PPh2(CH2)2PPh2)

Treatment of the thiosemicarbazone 2-FC6H4C(Me)= NN(H)C(=S)NHPh, a, with palladium(II) acetate in acetic acid, or with lithium tetrachloropalladate(II) in methanol, gave the tetranuclear cyclometallated complex [Pd{2-FC6H3C(Me)=NN= C(S)NHPh}]4 (1a). Reaction of 1a with the diphosphines Ph2P(CH2) 2PPh2 (dppe), Ph2PCH=CHPPh2 (trans-dpe) Ph2P(CH2)3Ph2 (dppp) or Ph2P(CH2)4Ph2 (dppb) in a 1:2 molar ratio gave the dinuclear cyclometallated complexes [(Pd{2-FC6H 3C(Me)=NN=C(S)NHPh})2(μ-Ph2P(CH 2)nPPh2)], (n = 2, 2a; 3, 4a; 4, 5a) and [(Pd{2-FC6H3C(Me)=NN=C(S)NHPh})2(μ-Ph 2PCH=CHPPh2)], (3a). The X-ray crystal structure of ligand a and of complex 2a are described. The structure of complex 2a shows the palladium atom is bonded to four different donor atoms: C, N, S and P. © 2005 Wiley-VCH Verlag GmbH & Co. KGaA.

Co (II), Ni(II) and Cu(II) complexes with a new pendant armed macrocyclic ligand showing several π,π-interactions

A new ligand, L, bearing four cyanoethyl pendant groups has been synthesized by reaction of the precursor ligand L 1 with acrylonitrile. The X-ray crystal structure of ligand L reveals the presence of a nanotubular structure in the solid state connected by intermolecular π,π-stacking interactions between adjacent pyridine rings. The coordination capability towards transition metal ions [Co(II), Ni(II) and Cu(II)] has been investigated starting from the hydrated nitrate and perchlorate salts of the metals. The new ligand L and the metal complexes obtained were characterized by elemental analysis, FAB MS, conductivity measurements, magnetic studies, IR and UV–vis spectroscopy. Furthermore, the crystal structure of ligand L and of the complexes [CoL][Co(NO 3) 4] · CH 3CN ( 1), [NiL](NO 3) 2 ( 3), [NiL](ClO 4) 2 · CH 3CN · 3H 2O ( 4), [CuL][Cu(NO 3) 3(H 2O) 2](NO 3) · H 2O ( 5) and [CuL](ClO 4) 2 · 2CH 3CN ( 6) were determined. The nitrate ions in the complexes are located near the pyridine rings and π,π-stacking interactions between pyridine rings, nitrate ions and nitrile groups have been found.

Structures of nitroso- and nitroguanidine X-ray crystallography and computational analysis

The X-ray structures of solid nitroguanidine (ngoH):orthorhombic, Fdd2, a = 17.6181(14), b = 24.848(2), c = 3.5901(4) A, V = 1571.7(3) A3, Z = 16 and nitrosoguanidine (ngH); monoclinic, P 21/n, a = 3.64510(10), b = 11.746(2), c = 8.6483(14) A, β = 99.167(2)∘, V = 365.55(9) A3, Z = 4 have been determined utilizing single crystal X-ray diffraction methods. The results are compared with the most stable gaseous configurations derived from ab inito calculations. The lowest energy calculated configuration for the ligands and experimentally observed crystal structures are in excellent agreement. In the solid state, both the ngoH and ngH contain discrete molecules in their unit cells which are planar (within experimental error), in the diamine configurations and are structurally identical except for an oxygen atom. In solid ngH, two ligand molecules have four nitrogen atoms arranged in a plane such that they are suitable for coordination to a nickel ion (1.945, 2.064 A), when it is at the 1/2, 1/2, 1/2 unit-cell position giving the observed complex. As far as we are aware, this is the first instance in which a ligand crystal structure is essentially the same, with minor distance, angle and torsion angle changes, as the complex it forms and suggests some potentially unique properties and applications for this material.

Structure of the nitrosoguanidine complexes of nickel(II) and copper(II) by X-ray crystallography and computational analysis

Using the X-ray structure of solid nitrosoguanidine (ngH), potential structures of its complex with aqueous nickel(II) were surmised. A single-crystal X-ray diffraction determination of the Ni(II) complex confirmed one of these configurations. The X-ray structural parameters were compared with the most stable gaseous configurations derived from ab initio-MO calculations. The lowest energy calculated configuration of the nickel(II) complex and the X-ray crystal structure are in excellent agreement. The neutral diamagnetic, planar, red-colored [bis(nitrosoguanidate)nickel(II)] complex, [Ni(ng)2]°, is nitrogen coordinated in the trans configuration. It is highly insoluble in all solvents investigated, and has essentially the same crystal symmetry and unit-cell dimensions as the free ligand. In ligand crystals, two molecules have four nitrogen atoms aligned in a plane such that they are suitable for coordination to a nickel ion (1.945, 2.064 Å), when it is at the 1/2, 1/2, 1/2 unit-cell position. Furthermore, the complexes stack, as in [Ni(dmg)2]°, placing the nickel ions in nearly perfect positions for weak metal–metal bonding between adjacent layers at the near optimum distance of 3.65(1) Å. This results in a tight, linear macromolecule having low volatility and the extremely low solubility observed. As far as we are aware this is the first instance in which a ligand crystal structure is essentially the same as the complex it forms, with minor differences in bond distances, angles and torsion angles, and suggests some potentially unique properties and applications for this material.

(2,5-diphenylphospholyl)-2-methylpyridine and 2-methyl-5R-phenyloxazoline PdCl 2 complexes: Syntheses, X-ray crystal structures and use in the Miyaura and Heck coupling reactions

Reaction of the (2,5-diphenylphospholyl)-2-methylpyridine ligand 1 with [PdCl 2 (COD)] affords the expected chelate complex 2, which was structurally characterized. Complex 2 catalyses the cross coupling reaction between pinacolborane and iodoaromatics to afford the corresponding arylboronic esters with TON up to 100 × 10 3 and with TON up to 90 × 10 2 in the case of bromoaromatics. The (2,5-diphenylphospholyl)-2-methyl-5 R-phenyloxazoline ligand 3 was synthesized by reaction of the 2,5-diphenylphospholide anion with 2-chloromethyl-5 R-phenyloxazoline in good yields. The [PdCl 2 (3)] complex 4 catalyses the asymmetric cross-coupling reaction between iodobenzene and 2,3-dihydrofuranne with low enantiomeric excess under classical conditions. X-ray crystal structures of ligand 3 and complex 4 were recorded. To cite this article: C. Thoumazet et al., C. R. Chimie 7 (2004) .

Synthesis, structural, physico-chemical and biological properties of new palladium(II) complexes with 2,6-dimethyl-4-nitropyridine

This paper describes the synthesis and properties of two new palladium(II) complexes with 2,6-dimethyl-4-nitro-pyridine (dmnp): mononuclear [Pd(dmnp) 2Cl 2] and dinuclear [Pd 2(dmnp) 2Cl 4]. Complexes were characterized on the basis of chemical and chromatographic analyses, MS and conductometric measurements, as well as by IR and NMR ( 1H and 13C) spectral studies. The crystal structures of ligand and mononuclear complex, trans-dichlorobis(2,6-dimethyl-4-nitro-pyridine)palladium(II), were determined by three-dimensional X-ray methods. The crystals of both compounds are monoclinic, space groups P2 1/ c with a=19.075(4), b=5.419(1), c=15.045(3) Å and β=108.15(3)° for (dmnp), and a=7.544(2), b=14.509(3), c=8.032(2) Å and β=90.32(3)° for [Pd(dmnp) 2Cl 2]. In the (dmnp) there are two crystallographically independent molecules in the unit cell. The nitro groups and methyl C atoms are coplanar with the ring plane. The hydrogen bond of the type C–H⋯O links the molecules into pairs around center of symmetry. These dimers are held together by contacts of the van der Waals type. In the crystal structure of [Pd(dmnp) 2Cl 2] the Pd atom lies on an inversion center and is four-coordinated by two pyridine N atoms and by two Cl atoms in trans positions. The coordination geometry is square-planar, with Pd–N and Pd–Cl distances of 2.033(2) and 2.311(1) Å, respectively. The two pyridine rings are mutually parallel, but they are twisted from the PdN2Cl2 coordination plane by about 88.5°. The preliminary assessments of anti-tumor properties of both complexes and ligand were evaluated as in vitro anti-proliferative activity in four human cancer cell lines: SW707 (adenocarcinoma of the rectum), T47D (breast cancer), HCV (bladder cancer) and A549 (non-small cell lung carcinoma). The [Pd(dmnp) 2Cl 2] exhibits strong cytotoxic activity against all cell lines whereas the free ligand and dinuclear [Pd 2(dmnp) 2Cl 4] are only moderate active.

Synthesis and X-ray crystal structure of a bridging trispiran ligand

Spiro(3,3)heptane-2,6-dispiro-4,5-diazafluorene (4) has been synthesized in three steps from 1,10-phenanthroline. It crystallizes in the orthorhombic space group P212121 and has the two 4,5-diazafluorene metal binding domains mutually orthogonal.

4 ′-(Oxodiphenylphosphino)-2,2 ′:6 ′,2 ′′-terpyridine – crystal structure and complexes of cobalt(II) and cobalt(III)

The complex [Co( 2) 2] 2+ ( 2 = 4 ′-(oxodiphenylphosphino)-2,2 ′:6 ′,2 ′′-terpyridine) has been prepared either by the direct reaction of 2 with Co(II) or by careful oxidation of [Co( 1) 2] 2+( 1 = 4 ′-(diphenylphosphino)-2,2 ′:6 ′,2 ′′-terpyridine). Further oxidation with H 2O 2 leads to [Co( 2) 2] 3+. The 1H NMR spectra of the paramagnetic and diamagnetic [Co( 2) 2] 2+ and [Co( 2) 2] 3+ are reported. The crystal structure of ligand 1 has been determined; in the solid-state, 1 exhibits extensive intermolecular π–π stacking.

Synthesis of trans‐disubstituted cyclam ligands appended with two 6‐hydroxymethylpyridin‐2‐ylmethyl sidearms: Crystal structures of the 1,8‐dimethyl‐4,ll‐di(6‐hydroxymethylpyridin‐2‐ylmethyl)cylam ligand and its Co(II) and Ni(II) complexes

AbstractTwo new trans‐disubstituted cyclam ligands; 1,8‐di(6‐hydroxymethylpyridin‐2‐ylmethyl)‐1,4,8,11‐tetra‐azacyclotetradecane (5) and 1,8‐dimethyl‐4, 11‐di(6‐hydroxymethylpyridin‐2‐ylmethyl)‐1,4,8,11 ‐tetraaza‐cyclotetradecane (6); have been synthesized and characterized. The crystal structures of ligand 6 and its Ni(II) and Co(II) complexes have been determined. Crystal data are given for 6, space group, P21/c, a = 11.095 (6) Å, b = 9.467 (5) Å, c = 13.283 (8) Å; β = 106.95 (5)°, Z = 2, R = 0.0715; for [Ni 6](C104)2, space group P21/c, a = 9.4848 (14) Å, b = 33.941(6) Å, c = 9.793(2) A, β = 95.264(14)°, Z = 4, R = 0.0567; for [Co 6](C104)2, space group, P21/c, a = 9.440 (6) Å, b = 33.848 (13) Å, c = 9.820 (3) Å, β = 95.16(3)°, Z = 4, R = 0.0718. In both complexes, the metal atoms are six‐coordinate with only one of the pendants interacting with the central metal atom and the other pendant remaining uncoordinated.

Lanthanide Triple Helical Complexes with a Chiral Bis(benzimidazole)pyridine Derivative

The ligand neopentyl 2,6-bis[(1-methylbenzimidazol-2-yl)]pyridine-4-carboxylate (L 12 ) has been synthesised to test the effect of the chiral neopentyl ester group in the 4-position of the pyridine ring on (i) the helical wrapping, (ii) the diastereomeric induction and (iii) the thermodynamic and photophysical properties of the [Ln(L 12 )3] 3+ complexes. The crystal structure of ligand L 12 shows the expected trans-trans conformation of the tridentate binding unit. The ligand forms stable 1:3 complexes in anhydrous acetonitrile (logβ3 in the range 17.3−19.0, logK3 in the range 2.9−4.6). The triple helical structure in solution is responsible for the four times

Carbonyl clusters with a capping methylidyne phosphonate ligand crystal structure of [CO 3(CO) 9{ η1- μ3-[CP(O) (OEt) 2]}

The bridging methylidyne clusters [Co 3(CO) 9{ η 1- μ 3-[CP(O)(OR) 2])] 1 (R = Et) and 3 (R = SiMe 3) with α-phosphoryl substituents have been synthesized by reaction of Cl 3C-P(O)(OR) 2 with Co 2(CO) 8, followed by protonation. Cluster 3 was also obtained by the reaction of 1 with Me 3SiBr. The structure of 1 has been determined by X-ray crystallography. The donor properties of the P=O function toward Lewis acids such as [Cp 2MCl] + (M = Ti, Zr) were used to assemble early—late metal systems.

The assignment of carbon monoxide association rate constants to the alpha and beta subunits in native and mutant human deoxyhemoglobin tetramers.

The association kinetics of CO binding to site-directed mutants of human deoxyhemoglobin were measured by stopped-flow rapid mixing techniques at pH 7.0, 20 degrees C. Hemoglobin tetramers were constructed from one set of native subunits and one set of mutated partners containing His(E7) to Gly, Val(E11) to Ala, or Val(E11) to Ile substitutions. The reactivity of beta Cys93 with p-hydroxymercuribenzoate was measured to ensure that the mutant deoxyhemoglobins were capable of forming T-state quaternary conformations. Time courses for the complete binding of CO were measured by mixing the deoxygenated proteins with a 5-fold excess of ligand in the absence and presence of inositol hexaphosphate. Association rate constants for the individual alpha and beta subunits in the T-state conformation were assigned by measuring time courses for the reaction of a small, limiting amount of CO with a 20-fold excess of deoxyhemoglobin (i.e. Hb4 + CO----Hb4(CO)). The effects of the E7 and E11 mutations in T-state alpha subunits were qualitatively similar to those observed for the same subunit in the R-state (Mathews, A.J., Rohlfs, R.J., Olson, J.S., Tame, J., Renaud, J-P., and Nagai, K. (1989) J. Biol. Chem. 264, 16573-16583). The alpha His58(E7) to Gly and Val62(E11) to Ala substitutions caused 80- and 3-fold increases, respectively, in k'CO for T-state alpha subunits, and the alpha Val62(E11) to Ile mutation caused a 3-fold decrease. The beta His63(E7) to Gly and Val67(E11) to Ala substitutions produced 70- and 8-fold increases, respectively, in k'CO for T-state beta subunits whereas these same mutations caused little effect on the rate of CO binding to R-state beta subunits. The beta Val67(E11) to Ile mutation produced the same large effect, a 23-fold reduction in k'CO, in both quaternary conformations of beta subunits. These kinetic results can be interpreted qualitatively in terms of differences between the alpha and beta subunits in the deoxy and liganded crystal structures of human hemoglobin (Perutz, M.F. (1990) Annu. Rev. Physiol. 52, 1-25). Both the structural and functional data suggest that the distal portion of the beta heme pocket is tightly packed in deoxyhemoglobin whereas the CO binding site in R-state beta subunits is much more open. In contrast, the distal portion of the alpha heme pocket is restricted sterically in both quaternary states.(ABSTRACT TRUNCATED AT 400 WORDS)

ChemInform Abstract: THE CRYSTAL AND MOLECULAR STRUCTURE OF A VERSATILE BIDENTATE LIGAND: TETRAPHENYLDITHIOIMIDODIPHOSPHINATE, PH2(S)PNHP(S)PH2

Chemischer InformationsdienstVolume 16, Issue 16 Physical Organic Chemistry ChemInform Abstract: THE CRYSTAL AND MOLECULAR STRUCTURE OF A VERSATILE BIDENTATE LIGAND: TETRAPHENYLDITHIOIMIDODIPHOSPHINATE, PH2(S)PNHP(S)PH2 P. B. HITCHCOCK, P. B. HITCHCOCKSearch for more papers by this authorJ. F. NIXON, J. F. NIXONSearch for more papers by this authorI. SILAGHI-DUMITRESCU, I. SILAGHI-DUMITRESCUSearch for more papers by this authorI. HAIDUC, I. HAIDUCSearch for more papers by this author P. B. HITCHCOCK, P. B. HITCHCOCKSearch for more papers by this authorJ. F. NIXON, J. F. NIXONSearch for more papers by this authorI. SILAGHI-DUMITRESCU, I. SILAGHI-DUMITRESCUSearch for more papers by this authorI. HAIDUC, I. HAIDUCSearch for more papers by this author First published: April 23, 1985 https://doi.org/10.1002/chin.198516076AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume16, Issue16April 23, 1985 RelatedInformation

Synthesis, and X-ray crystal and molecular structure of a novel macro-bicyclic ligand: crowned p-t-butyl-calix[4]arene

Capping of p-t-butyl-calix[4]arene (1a) with pentaethylene glycol ditoluene-p-sulphonate and ButOK in benzene leads to the first member of a new class of macrobicyclic crown compounds (2), which possess two cavities (one hydrophilic and one lypophilic) and two additional, ionizable binding sites.