Farnesyl pyrophosphate synthase (FPPS) is the major molecular target of nitrogen-containing bisphosphonates (N-BPs), used clinically as bone resorption inhibitors. We investigated the role of threonine 201 (Thr201) and tyrosine 204 (Tyr204) residues in substrate binding, catalysis and inhibition by N-BPs, employing kinetic and crystallographic studies of mutated FPPS proteins. Mutants of Thr201 illustrated the importance of the methyl group in aiding the formation of the Isopentenyl pyrophosphate (IPP) binding site, while Tyr204 mutations revealed the unknown role of this residue in both catalysis and IPP binding. The interaction between Thr201 and the side chain nitrogen of N-BP was shown to be important for tight binding inhibition by zoledronate (ZOL) and risedronate (RIS), although RIS was also still capable of interacting with the main-chain carbonyl of Lys200. The interaction of RIS with the phenyl ring of Tyr204 proved essential for the maintenance of the isomerized enzyme-inhibitor complex. Studies with conformationally restricted analogues of RIS reaffirmed the importance of Thr201 in the formation of hydrogen bonds with N-BPs. In conclusion we have identified new features of FPPS inhibition by N-BPs and revealed unknown roles of the active site residues in catalysis and substrate binding.

Matrix metalloproteinase (MMP) inhibitors are potential therapeutic agents for various diseases including cancer and osteoarthritis. Recent data from clinical trials with MMP inhibitors indicate that there is a great need for selective inhibitors. X-ray crystallography [1], [2], [3] has been used as a tool to help understand specific binding interactions of inhibitors to various MMPs. Large conformational changes have been noted when comparing the structures of the active MMP-3 catalytic domain and the one inhibited by a hydroxamic acid inhibitor. Both soaking and co-crystallization methods were used to generate the MMP-3/ inhibitor complex crystals for data collection. The same inhibitor has also been co-crystallized with MMP-1 and MMP-13. Comparisons of the structures of three inhibited enzymes, MMP-1, 3, and 13 show that MMP-3 and 13 are extremely similar. There are major differences in the binding pockets, especially in the S1’ pocket between MMP-1 and MMP-3/13. These structural studies have helped design more selective inhibitors that can be used as therapeutic agents with improved safety profile.

The ability of bisphosphonates ((HO)(2)P(O)CR(1)R(2)P(O)(OH)(2)) to inhibit bone resorption has been known since the 1960s, but it is only recently that a detailed molecular understanding of the relationship between chemical structures and biological activity has begun to emerge. The early development of chemistry in this area was largely empirical and based on modifying R(2) groups in a variety of ways. Apart from the general ability of bisphosphonates to chelate Ca(2+) and thus target the calcium phosphate mineral component of bone, attempts to refine clear structure-activity relationships had led to ambiguous or seemingly contradictory results. However, there was increasing evidence for cellular effects, and eventually the earliest bisphosphonate drugs, such as clodronate (R(1)=R(2)=Cl) and etidronate (R(1)=OH, R(2)=CH(3)), were shown to exert intracellular actions via the formation in vivo of drug derivatives of ATP. The observation that pamidronate, a bisphosphonate with R(1)=OH and R(2)=CH(2)CH(2)NH(2), exhibited higher potency than previously known bisphosphonate drugs represented the first step towards the later recognition of the critical importance of having nitrogen in the R(2) side chain. The synthesis and biological evaluation of a large number of nitrogen-containing bisphosphonates took place particularly in the 1980s, but still with an incomplete understanding of their structure-activity relationships. A major advance was the discovery that the anti-resorptive effects of the nitrogen-containing bisphosphonates (including alendronate, risedronate, ibandronate, and zoledronate) on osteoclasts appear to result from their potency as inhibitors of the enzyme farnesyl pyrophosphate synthase (FPPS), a key branch-point enzyme in the mevalonate pathway. FPPS generates isoprenoid lipids utilized in sterol synthesis and for the post-translational modification of small GTP-binding proteins essential for osteoclast function. Effects on other cellular targets, such as osteocytes, may also be important. Over the years many hundreds of bisphosphonates have been synthesized and studied. Interest in expanding the structural scope of the bisphosphonate class has also motivated new approaches to the chemical synthesis of these compounds. Recent chemical innovations include the synthesis of fluorescently labeled bisphosphonates, which has enabled studies of the biodistribution of these drugs. As a class, bisphosphonates share common properties. However, as with other classes of drugs, there are chemical, biochemical, and pharmacological differences among the individual compounds. Differences in mineral binding affinities among bisphosphonates influence their differential distribution within bone, their biological potency, and their duration of action. The overall pharmacological effects of bisphosphonates on bone, therefore, appear to depend upon these two key properties of affinity for bone mineral and inhibitory effects on osteoclasts. The relative contributions of these properties differ among individual bisphosphonates and help determine their clinical behavior and effectiveness.

Aminomethyltransferase, a component of the glycine cleavage system termed T-protein, reversibly catalyzes the degradation of the aminomethyl moiety of glycine attached to the lipoate cofactor of H-protein, resulting in the production of ammonia, 5,10-methylenetetrahydrofolate, and dihydrolipoate-bearing H-protein in the presence of tetrahydrofolate (THF).Several mutations in the human T-protein gene are known to cause non-ketotic hyperglycinemia.Previously we determined the

Bispecific antibodies have been successfully introduced into clinical application. γδ T cells are of special interest for tumor immunotherapy, due to their recognition of pyrophosphates that are overproduced by many tumor cells resulting in HLA-nonrestricted tumor cell killing. Here we describe in detail a [(Her2)2 × Vγ9] tribody construct that targets human Vγ9 T cells to HER2-expressing tumor cells. The direct comparison with other selective Vγ9 T cell agonists including phosphoantigens and nitrogen-containing bisphosphonates revealed the superiority of the [(Her2)2 × Vγ9] tribody in triggering γδ T cell-mediated tumor cell killing with negligible induction of γδ T cell death. In contrast, phosphoantigens and bisphosphonates are potent inducers of γδ T cell proliferation but less efficient enhancers of γδ T cell-mediated tumor cell killing. Collectively, our data identify unique properties of a γδ T cell-targeting [(Her2)2 × Vγ9] tribody which make it an attractive candidate for clinical application in γδ T cell-based tumor immunotherapy.

Osteoporosis is an asymptomatic progressive disease. With the improvement of people's living standard and the aging of population, osteoporosis and its fracture have become one of the main diseases threatening the aging society. The serious medical and social burden caused by this has aroused wide public concern. Osteoporosis is listed as one of the three major diseases of the elderly. At present, the drugs for osteoporosis include bone resorption inhibitors and bone formation promoters. The purpose of these anti-osteoporosis drugs is to balance osteoblast bone formation and osteoclast bone resorption. With the development of anti-osteoporosis drugs, new anti osteoporosis drugs have been designed and synthesized. There are many kinds of new compounds with anti osteoporosis activity, but most of them are concentrated on the original drugs with anti osteoporosis activity, or the natural products with anti-osteoporosis activity are extracted from the natural products for structural modification to obtain the corresponding derivatives or analogues. These target compounds showed good ALP activity in vitro and in vivo, promoted osteoblast differentiation and mineralization, or had anti TRAP activity, inhibited osteoclast absorption. This work attempts to systematically review the studies on the synthesis and bioactivity of anti-osteoporosis drugs in the past 10 years. The structure-activity relationship was discussed, which provided a reasonable idea for the design and development of new anti-osteoporosis drugs.

The complex formed from crystallization of human farnesyl pyrophosphate synthase (hFPPS) from a solution of racemic [6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl(hydroxy)methylene]bis(phosphonic acid) (NE-10501, 8), a chiral analog of the anti-osteoporotic drug risedronate, contained the R enantiomer in the enzyme active site. This enantiospecificity was assessed by computer modeling of inhibitor-active site interactions using Autodock 3, which was also evaluated for predictive ability in calculations of the known configurations of risedronate, zoledronate, and minodronate complexed in the active site of hFPPS. In comparison with these structures, the 8 complex exhibited certain differences, including the presence of only one Mg(2+), which could contribute to its 100-fold higher IC(50). An improved synthesis of 8 is described, which decreases the number of steps from 12 to 8 and increases the overall yield by 17-fold.

The nitrogen-containing bisphosphonates (N-BPs) are the main drugs currently used to treat diseases characterized by excessive bone resorption. The major molecular target of N-BPs is farnesylpyrophosphate synthase. N-BPs inhibit the enzyme by a mechanism that involves time dependent isomerization of the enzyme. We investigated features of N-BPs that confer maximal slow and tight-binding by quantifying the initial and final K(i)s and calculating the isomerization constant K(isom) for many N-BPs. Disruption of the phosphonate-carbon-phosphonate backbone resulted in loss of potency and reduced K(isom). The lack of a hydroxyl group on the geminal carbon also reduced K(isom). The position of the nitrogen in the side chain was crucial to both K(i) and K(isom). A correlation of K(isom) and also final K(i) with previously published in vivo potency reveals that the isomerization constant ( R = -0.77, p < 0.0001) and the final inhibition of FPPS by N-BPs ( R = 0.74, p < 0.0001) are closely linked to antiresorptive efficacy.

In this article we describe the application of structural biology methods to the discovery of novel potent inhibitors of methionine aminopeptidases. These enzymes are employed by the cells to cleave the N‐terminal methionine from nascent peptides and proteins. As this is one of the critical steps in protein maturation, it is very likely that inhibitors of these enzymes may prove useful as novel antibacterial agents. Involvement of crystallography at the very early stages of the inhibitor design process resulted in serendipitous discovery of a new inhibitor class, the pyrazole‐diamines. Atomic‐resolution structures of several inhibitors bound to the enzyme illuminate a new mode of inhibitor binding. Proteins 2007. © 2006 Wiley‐Liss, Inc.

The bisphosphonates (BPs) are well established as the treatments of choice for disorders of excessive bone resorption, including Paget's disease of bone, myeloma and bone metastases, and osteoporosis. There is considerable new knowledge about how BPs work. Their classical pharmacological effects appear to result from two key properties: their affinity for bone mineral and their inhibitory effects on osteoclasts. Mineral binding affinities differ among the clinically used BPs and may influence their differential distribution within bone, their biological potency, and their duration of action. The inhibitory effects of the nitrogen-containing BPs (including alendronate, risedronate, ibandronate, and zoledronate) on osteoclasts appear to result from their inhibition of farnesyl pyrophosphate synthase (FPPS), a key branch-point enzyme in the mevalonate pathway. FPPS generates isoprenoid lipids used for the post-translational modification of small GTP-binding proteins essential for osteoclast function. Effects on other cellular pathways, such as preventing apoptosis in osteocytes, are emerging as other potentially important mechanisms of action. As a class, BPs share several common properties. However, as with other classes of drugs, there are obvious chemical, biochemical, and pharmacological differences among the various individual BPs. Each BP has a unique profile that may help to explain potential important clinical differences among the BPs, in terms of speed of onset of fracture reduction, antifracture efficacy at different skeletal sites, and the degree and duration of suppression of bone turnover. As we approach the 40th anniversary of the discovery of their biological effects, there remain further opportunities for using their properties for medical purposes.

AbstractThe Bonding in a Three‐center Hydrogen‐bridged Ni‐Ni System.

Chemischer InformationsdienstVolume 11, Issue 5 Reviews ChemInform Abstract: STRUCTURE AND BONDING IN ORGANIC IRON COMPOUNDS C. KRUEGER, C. KRUEGERSearch for more papers by this authorB. L. BARNETT, B. L. BARNETTSearch for more papers by this authorD. BRAUER, D. BRAUERSearch for more papers by this author C. KRUEGER, C. KRUEGERSearch for more papers by this authorB. L. BARNETT, B. L. BARNETTSearch for more papers by this authorD. BRAUER, D. BRAUERSearch for more papers by this author First published: February 5, 1980 https://doi.org/10.1002/chin.198005395AboutPDF 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 onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References C. KRUEGER, B. L. BARNETT, D. BRAUER, STRUCTURE AND BONDING IN ORGANIC IRON COMPOUNDS, Org. Chem. Iron. Google Scholar Volume11, Issue5February 5, 1980 ReferencesRelatedInformation

AbstractThe crystal structure of the title compound, [(C6H11)2PCH2CH2CH2P(C6H11)2NiH]2 (1), has been determined from 4051 reflections and refined to a final R‐value of 0.044. The positions of the hydrogen atoms (bridging and non‐bridging) have been determined from a difference Fourier synthesis. The molecular structure of the diamagnetic compound consists of subunits doubly‐bridged by hydrogen atoms. The NiNi and average NiH distances are 2.441 and 1.6 Å, respectively. In the solid state the two planes of the P2Ni units form a dihedral angle of 63.3°. Theoretical considerations predict a square‐planar structure for the idealized molecule with a soft potential energy surface for a twisting motion towards the observed geometry. The observed twist is the result of severe intramolecular repulsions between the cyclohexyl groups of the two P2Ni units.

Chemischer InformationsdienstVolume 6, Issue 30 Organoelement Compounds ChemInform Abstract: CRYSTAL AND MOLECULAR STRUCTURE OF TETRAKIS-(2,2,6,6-TETRAMETHYL-3,5-HEPTANEDIONATO)NIOBIUM(IV), A SQUARE ANTIPRISMATIC M(BIDENTATE)4 STEREOISOMER T. J. PINNAVAIA, T. J. PINNAVAIASearch for more papers by this authorBOBBY L. BARNETT, BOBBY L. BARNETTSearch for more papers by this authorGEORGE PODOLSKY, GEORGE PODOLSKYSearch for more papers by this authorA. TULINSKY, A. TULINSKYSearch for more papers by this author T. J. PINNAVAIA, T. J. PINNAVAIASearch for more papers by this authorBOBBY L. BARNETT, BOBBY L. BARNETTSearch for more papers by this authorGEORGE PODOLSKY, GEORGE PODOLSKYSearch for more papers by this authorA. TULINSKY, A. TULINSKYSearch for more papers by this author First published: July 29, 1975 https://doi.org/10.1002/chin.197530354AboutPDF 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. Volume6, Issue30July 29, 1975 RelatedInformation

AbstractDas Cyclobutadien‐Fe‐carbonyl (I) reagiert mit überschüssigem Dodekacarbonyltrieisen (II) in Kohlenwasserstoff‐Lösung zu den Benzoferrolen (III) und (IV), die IR‐ spektroskopisch sowie durch röntgenographisch ermittelte Kristallstrukturdaten charakterisiert werden.

The molecular conformation of two square planar π-pentenylnickel(II) complexes with σ and π nickelcarbon bonds, (π-pentenyl)(diisopropylphenylphosphine) methylnickel(II) and (π-pentenyl)(dimenthylmethylphosphine) methylnickel(II), have been determined from single crystal X-ray data collected at room temperature with counter methods. Molecule I crystallizes in the monoclinic space group P21/c with four molecules in a unit cell of the dimensions a 8.927(3),b 26,031(9),c 8.718(2)Å, β 110.88(2)°;II crystallizes in the orthorhombic system, space group P212121, with four molecules in a cell a 14.446(1) b 13.727(1), c 11.895(1)Å. Both structures have been refined anisotropically to R values of 6.26 and 3.65%, respectively. The absolute configuration of II has been determined to be R on a 99.5% confidence level. Comments are made on the bonding situation of the π-allylic fragments as well as on the steric conformation of the phosphine ligands. The NiC(σ) bond distances were found to be 1.99(1) in compound I and 1.975(4)Å in compound II.

Chemischer InformationsdienstVolume 5, Issue 51 Physical Organic Chemistry ChemInform Abstract: THE MOLECULAR CONFIGURATION OF TWO COMPLEXES WITH SIGMA AND PI NICKEL-CARBON BONDS, (PI-PENTENYL)(DIISOPROPYLPHENYLPHOSPHINE)METHYLNICKEL(II) AND (PI-PENTENYL)(DIMENTHYLMETHYLPHOSPHINE)METHYLNICKEL(II) B. L. BARNETT, B. L. BARNETTSearch for more papers by this authorC. KRUEGER, C. KRUEGERSearch for more papers by this author B. L. BARNETT, B. L. BARNETTSearch for more papers by this authorC. KRUEGER, C. KRUEGERSearch for more papers by this author First published: December 24, 1974 https://doi.org/10.1002/chin.197451112AboutPDF 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. Volume5, Issue51December 24, 1974 RelatedInformation

Chemischer InformationsdienstVolume 4, Issue 1 Physical Organic Chemistry ChemInform Abstract: DIE MOLEKUEL- UND KRISTALLSTRUKTUR VON (TRICYCLOHEXYLPHOSPHIN)-METHYLNICKEL(II)-2,4-PENTANDIONAT, EIN QUADRATISCH PLANARER KOMPLEX MIT EINER SIGMA-NICKEL-KOHLENSTOFF-BINDUNG B. L. BARNETT, B. L. BARNETTSearch for more papers by this authorC. KRUEGER, C. KRUEGERSearch for more papers by this author B. L. BARNETT, B. L. BARNETTSearch for more papers by this authorC. KRUEGER, C. KRUEGERSearch for more papers by this author First published: January 2, 1973 https://doi.org/10.1002/chin.197301098Read the full textAboutPDF 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 onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume4, Issue1January 2, 1973 RelatedInformation