Christof Wegscheid-Gerlach | Philipps Universität Marburg (original) (raw)
Papers by Christof Wegscheid-Gerlach
ChemMedChem, 2015
Pioneering inspiration: Right next to the former laboratories of Johannes Hartmann, the first so-... more Pioneering inspiration: Right next to the former laboratories of Johannes Hartmann, the first so-called "Professor of Chymiatrie", the 2015 Frontiers in Medicinal Chemistry meeting was held last March at Philipps University in Marburg, Germany. Herein we give readers an idea of what it was like to attend the conference, which was organized jointly by the DPhG, GDCh, and SCS. Along with the lectures, we also describe the poster sessions, social program, and awards.
ChemMedChem, 2014
Neuronal cell death is the main cause behind the progressive loss of brain function in age-relate... more Neuronal cell death is the main cause behind the progressive loss of brain function in age-related neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Despite the differing etiologies of these neurological diseases, the underlying neuronal damage is triggered by common mechanisms such as oxidative stress, impaired calcium homeostasis, and disrupted mitochondrial integrity and function. In particular, mitochondrial fragmentation, mitochondrial membrane permeability, and the release of death-promoting factors into the cytosol have been revealed as the "point of no return" in programmed cell death in neurons. Recent studies revealed a pivotal role for the pro-apoptotic Bcl-2-family protein Bid in models of neuronal cell death, which confirmed Bid as a potential drug target. Herein, we present N-acyl-substituted derivatives of 4-phenoxyaniline that were screened for their potential to attenuate Bid-mediated neurotoxicity. These compounds provided ...
The Journal of pharmacology and experimental therapeutics, 2014
Mitochondrial demise is a key feature of progressive neuronal death contributing to acute and chr... more Mitochondrial demise is a key feature of progressive neuronal death contributing to acute and chronic neurological disorders. Recent studies identified a pivotal role for the BH3-only protein B-cell lymphoma-2 interacting domain death antagonist (Bid) for such mitochondrial damage and delayed neuronal death after oxygen-glucose deprivation, glutamate-induced excitotoxicity, or oxidative stress in vitro and after cerebral ischemia in vivo. Therefore, we developed new N-phenyl-substituted thiazolidine-2,4-dione derivatives as potent inhibitors of Bid-dependent neurotoxicity. The new compounds 6, 7, and 16 were identified as highly protective by extensive screening in a model of glutamate toxicity in immortalized mouse hippocampal neurons (HT-22 cells). These compounds significantly prevent truncated Bid-induced toxicity in the neuronal cell line, providing strong evidence that inhibition of Bid was the underlying mechanism of the observed protective effects. Furthermore, Bid-dependent...
Current topics in medicinal chemistry, 2010
Pharmazie in unserer Zeit, 2009
Journal of Molecular Biology, 2011
A congeneric series of benzamidine-type ligands with a central proline moiety and a terminal cycl... more A congeneric series of benzamidine-type ligands with a central proline moiety and a terminal cycloalkyl group--linked by a secondary amine, ether, or methylene bridge--was synthesized as trypsin inhibitors. This series of inhibitors was investigated by isothermal titration calorimetry, crystal structure analysis in two crystal forms, and molecular dynamics simulations. Even though all of these congeneric ligands exhibited essentially the same affinity for trypsin, their binding profiles at the structural, dynamic, and thermodynamic levels are very distinct. The ligands display a pronounced enthalpy/entropy compensation that results in a nearly unchanged free energy of binding, even though individual enthalpy and entropy terms change significantly across the series. Crystal structures revealed that the secondary amine-linked analogs scatter over two distinct conformational families of binding modes that occupy either the inside or of the outside the protein's S3/S4 specificity pocket. In contrast, the ether-linked and methylene-linked ligands preferentially occupy the hydrophobic specificity pocket. This also explains why the latter ligands could only be crystallized in the conformationally restricting closed crystal form whereas the derivative with the highest residual mobility in the series escaped our attempts to crystallize it in the closed form; instead, a well-resolved structure could only be achieved in the open form with the ligand in disordered orientation. These distinct binding modes are supported by molecular dynamics simulations and correlate with the shifting enthalpic/entropic signatures of ligand binding. The examples demonstrate that, at the molecular level, binding modes and thermodynamic binding signatures can be very different even for closely related ligands. However, deviating binding profiles provide the opportunity to optimally address a given target.
Current Topics in Medicinal Chemistry, 2010
Malaria, caused by protozoa of the genus Plasmodium, remains one of the most dreadful infectious ... more Malaria, caused by protozoa of the genus Plasmodium, remains one of the most dreadful infectious diseases worldwide killing more than 1 million people per year. The emergence of multidrug-resistant parasites highly demands a steadfast and continuous search not only for new targets but also for new anti-infectives addressing the known ones. As proteases in general have been proven to be excellent drug targets and the development of inhibitors has frequently resulted in approved drugs, this review will only focus on the proteases of Plasmodium falciparum as drug targets. The completion of the sequencing of the Plasmodium falciparum genome in 2002 lead to the discovery of nearly 100 putative proteases encoded therein. Within this review, only those proteases and inhibitors thereof will be discussed in more detail, in which their biological function has been determined undoubtedly or in those cases, in which the development of specific inhibitors has significantly contributed to the understanding of the underlying biological role of the respective protease thus validating the role as promising drug target.
Current Topics in Medicinal Chemistry, 2010
ABSTRACT Members of the protease families discussed in this issue are of great interest for diffe... more ABSTRACT Members of the protease families discussed in this issue are of great interest for different therapeutic areas tackling contemporary afflictions of mankind such as cardiovascular, infective, or respiratory diseases as well as cancer. The proteases dealt with not only act as protein-degrading enzymes, their important function within signaling pathways makes them also highly attractive as valid drug targets. The search for as well as the identification of potent and selective inhibitors for this protein family has been very popular for decades and still is a highly competitive field in industrial and academic drug research development. This special issue of Current Topics in Medicinal Chemistry “The Medicinal Chemistry of Protease Inhibitors” focuses on inhibitors of different protease classes and is divided into three major parts: the first part discusses inhibitors for particular members of the threonine, serine, and cysteine protease family, the second gives an overview of proteases and their inhibitors involved in infectious diseases, and the third part reviews hit validation, conducting as well as pitfalls frequently occurring in protease assays. The issue starts with a review of Genin, Reboud-Ravaux, and Vidal on recent advances and new perspectives of proteasome inhibitors. The well-known covalent inhibitors for this member of the threonine protease family as well as recent developments towards first non-covalent derivatives are discussed. In the following, Straub, Rohrig, and Hillisch highlight the field of factor Xa, representing one example of the serine protease family, and its corresponding inhibitors. Their review concentrates on different non-basic P1-site inhibitors and describes in particular the development of Rivaroxaban (Xarelto™). The family of cysteine proteases and their inhibitors are presented within two contributions. Pietsch, Chua, and Abell introduce into the field of calpains as attractive drug targets and inhibitors thereof, followed by an article of Frizler, Stirnberg, Sisay, and Gütschow discussing nitrile-based peptidic inhibitors for the subfamily of cathepsins. The subsequent part of this issue focuses on proteases that are suitable drug targets to combat infectious diseases. The aim of this part is to give a survey of active compounds inhibiting proteases of different classes but share their quality of being active in only one therapeutic category. Steuber and Hilgenfeld describe the class of viral proteases which are investigated within the antiviral drug discovery. A second topic, summarized in a review of Wegscheid-Gerlach, Gerber and Diederich, deals with different malarial proteases of plasmodium falciparum and inhibitors thereof. In the final part of this issue, Ludewig, Kossner, Schiller, Baumann, and Schirmeister discuss in their contribution entitled “Enzyme kinetics and hit validation in fluorimetric protease assays” common problems frequently occurring in fluorimetric assays. They furthermore provide methods and strategies concerning problem solving as well as circumventive measures prior to assay determination. We very much appreciated the valuable contributions of all authors to this special issue of Current Topics in Medicinal Chemistry entitled “The Medicinal Chemistry of Protease Inhibitors”. We would also like to thank all reviewers for their very constructive comments. We are also grateful to the editor-in-chief, Dr. Allen Reitz, for the invitation and the opportunity to compile this special issue as guest editors and for all his support concerning the preparation of this special issue.
Fragment-based approaches have become very popular within the lead finding phase of a drug design... more Fragment-based approaches have become very popular within the lead finding phase of a drug design project. Different experimental techniques such as X-ray and NMR-supported protocols have been developed to detect and applied to successfully novel lead structures (1). In addition, in silico approaches considering either descriptor- (2), ligand- (3) or structure- based (4) information for navigating within chemical fragment spaces
Journal of Organometallic Chemistry, 2006
We have developed a short and highly efficient synthetic strategy towards the hitherto hardly kno... more We have developed a short and highly efficient synthetic strategy towards the hitherto hardly known 3,5-and 3,6-disubstituted 2,3,4,7tetrahydro-1H-azepine scaffold via a ring-closing metathesis approach utilizing inexpensive and readily available starting material such as methyl acrylate and allylamine. Both seven-membered azacycle scaffolds bearing suitable functional groups, which can easily be modified by means of standard synthetic chemistry, serve as non-peptidic heterocyclic core structures for the further design and synthesis of aspartic protease inhibitors. Through specific decoration with appropriate side chains, individual inhibitors can be tailored with respect to selectivity towards particular family members. A first generation of this class of non-peptidic inhibitors have been tested against the aspartic proteases Plasmepsin II and HIV-I protease, respectively, showing promising activity as well as selectivity with IC 50 values in the micromolar range.
Journal of Molecular Biology, 2006
In structure-based drug design, accurate crystal structure determination of protein-ligand comple... more In structure-based drug design, accurate crystal structure determination of protein-ligand complexes is of utmost importance in order to elucidate the binding characteristics of a putative lead to a given target. It is the starting point for further design hypotheses to predict novel leads with improved properties. Often, crystal structure determination is regarded as ultimate proof for ligand binding providing detailed insight into the specific binding mode of the ligand to the protein. This widely accepted practise relies on the assumption that the crystal structure of a given protein-ligand complex is unique and independent of the protocol applied to produce the crystals. We present two examples indicating that this assumption is not generally given, even though the composition of the mother liquid for crystallisation was kept unchanged: Multiple crystal structure determinations of aldose reductase complexes obtained under varying crystallisation protocols concerning soaking and crystallisation exposure times were performed resulting in a total of 17 complete data sets and ten refined crystal structures, eight in complex with zopolrestat and two complexed with tolrestat. In the first example, a flip of a peptide bond is observed, obviously depending on the crystallisation protocol with respect to soaking and co-crystallisation conditions. This peptide flip is accompanied by a rupture of an H-bond formed to the bound ligand zopolrestat. The indicated enhanced local mobility of the complex is in agreement with the results of molecular dynamics simulations. As a second example, the aldose reductase-tolrestat complex is studied. Unexpectedly, two structures could be obtained: one with one, and a second with four inhibitor molecules bound to the protein. They are located in and near the binding pocket facilitated by crystal packing effects. Accommodation of the four ligand molecules is accompanied by pronounced shifts concerning two helices interacting with the additional ligands.
Journal of Molecular Biology, 2009
The field of medicinal chemistry aims to design and optimize small molecule leads into drug candi... more The field of medicinal chemistry aims to design and optimize small molecule leads into drug candidates that may positively interfere with pathological disease situations in humans or combat the growth of infective pathogens. From the plethora of crystal structures of protein-inhibitor complexes we have learned how molecules recognize each other geometrically, but we still have rather superficial understanding of why they bind to each other. This contribution surveys a series of 26 thrombin inhibitors with small systematic structural differences to elucidate the rationale for their widely deviating binding affinity from 185 microM to 4 nM as recorded by enzyme kinetic measurements. Five well-resolved (resolution 2.30 - 1.47 A) crystal structures of thrombin-inhibitor complexes and an apo-structure of the uncomplexed enzyme (1.50 A) are correlated with thermodynamic data recorded by isothermal titration calorimetry with 12 selected inhibitors from the series. Taking solubility data into account, the variation in physicochemical properties allows conclusions to be reached about the relative importance of the enthalpic binding features as well as to estimate the importance of the parameters more difficult to capture, such as residual ligand entropy and desolvation properties. The collected data reveal a comprehensive picture of the thermodynamic signature that explains the so far poorly understood attractive force experienced by m-chloro-benzylamides to thrombin.
Journal of Computer-Aided Molecular Design, 2008
FTrees (FT) is a known chemoinformatic tool able to condense molecular descriptions into a graph ... more FTrees (FT) is a known chemoinformatic tool able to condense molecular descriptions into a graph object and to search for actives in large databases using graph similarity. The query graph is classically derived from a known active molecule, or a set of actives, for which a similar compound has to be found. Recently, FT similarity has been extended to fragment space, widening its capabilities. If a user were able to build a knowledge-based FT query from information other than a known active structure, the similarity search could be combined with other, normally separate, fields like de-novo design or pharmacophore searches. With this aim in mind, we performed a comprehensive analysis of several databases in terms of FT description and provide a basic statistical analysis of the FT spaces so far at hand. Vendors' catalogue collections and MDDR as a source of potential or known "actives", respectively, have been used. With the results reported herein, a set of ranges, mean values and standard deviations for several query parameters are presented in order to set a reference guide for the users. Applications on how to use this information in FT query building are also provided, using a newly built 3D-pharmacophore from 57 5HT-1F agonists and a published one which was used for virtual screening for tRNA-guanine transglycosylase (TGT) inhibitors.
Angewandte Chemie International Edition, 2007
Angewandte Chemie International Edition, 2007
ChemMedChem, 2015
Pioneering inspiration: Right next to the former laboratories of Johannes Hartmann, the first so-... more Pioneering inspiration: Right next to the former laboratories of Johannes Hartmann, the first so-called "Professor of Chymiatrie", the 2015 Frontiers in Medicinal Chemistry meeting was held last March at Philipps University in Marburg, Germany. Herein we give readers an idea of what it was like to attend the conference, which was organized jointly by the DPhG, GDCh, and SCS. Along with the lectures, we also describe the poster sessions, social program, and awards.
ChemMedChem, 2014
Neuronal cell death is the main cause behind the progressive loss of brain function in age-relate... more Neuronal cell death is the main cause behind the progressive loss of brain function in age-related neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Despite the differing etiologies of these neurological diseases, the underlying neuronal damage is triggered by common mechanisms such as oxidative stress, impaired calcium homeostasis, and disrupted mitochondrial integrity and function. In particular, mitochondrial fragmentation, mitochondrial membrane permeability, and the release of death-promoting factors into the cytosol have been revealed as the "point of no return" in programmed cell death in neurons. Recent studies revealed a pivotal role for the pro-apoptotic Bcl-2-family protein Bid in models of neuronal cell death, which confirmed Bid as a potential drug target. Herein, we present N-acyl-substituted derivatives of 4-phenoxyaniline that were screened for their potential to attenuate Bid-mediated neurotoxicity. These compounds provided ...
The Journal of pharmacology and experimental therapeutics, 2014
Mitochondrial demise is a key feature of progressive neuronal death contributing to acute and chr... more Mitochondrial demise is a key feature of progressive neuronal death contributing to acute and chronic neurological disorders. Recent studies identified a pivotal role for the BH3-only protein B-cell lymphoma-2 interacting domain death antagonist (Bid) for such mitochondrial damage and delayed neuronal death after oxygen-glucose deprivation, glutamate-induced excitotoxicity, or oxidative stress in vitro and after cerebral ischemia in vivo. Therefore, we developed new N-phenyl-substituted thiazolidine-2,4-dione derivatives as potent inhibitors of Bid-dependent neurotoxicity. The new compounds 6, 7, and 16 were identified as highly protective by extensive screening in a model of glutamate toxicity in immortalized mouse hippocampal neurons (HT-22 cells). These compounds significantly prevent truncated Bid-induced toxicity in the neuronal cell line, providing strong evidence that inhibition of Bid was the underlying mechanism of the observed protective effects. Furthermore, Bid-dependent...
Current topics in medicinal chemistry, 2010
Pharmazie in unserer Zeit, 2009
Journal of Molecular Biology, 2011
A congeneric series of benzamidine-type ligands with a central proline moiety and a terminal cycl... more A congeneric series of benzamidine-type ligands with a central proline moiety and a terminal cycloalkyl group--linked by a secondary amine, ether, or methylene bridge--was synthesized as trypsin inhibitors. This series of inhibitors was investigated by isothermal titration calorimetry, crystal structure analysis in two crystal forms, and molecular dynamics simulations. Even though all of these congeneric ligands exhibited essentially the same affinity for trypsin, their binding profiles at the structural, dynamic, and thermodynamic levels are very distinct. The ligands display a pronounced enthalpy/entropy compensation that results in a nearly unchanged free energy of binding, even though individual enthalpy and entropy terms change significantly across the series. Crystal structures revealed that the secondary amine-linked analogs scatter over two distinct conformational families of binding modes that occupy either the inside or of the outside the protein's S3/S4 specificity pocket. In contrast, the ether-linked and methylene-linked ligands preferentially occupy the hydrophobic specificity pocket. This also explains why the latter ligands could only be crystallized in the conformationally restricting closed crystal form whereas the derivative with the highest residual mobility in the series escaped our attempts to crystallize it in the closed form; instead, a well-resolved structure could only be achieved in the open form with the ligand in disordered orientation. These distinct binding modes are supported by molecular dynamics simulations and correlate with the shifting enthalpic/entropic signatures of ligand binding. The examples demonstrate that, at the molecular level, binding modes and thermodynamic binding signatures can be very different even for closely related ligands. However, deviating binding profiles provide the opportunity to optimally address a given target.
Current Topics in Medicinal Chemistry, 2010
Malaria, caused by protozoa of the genus Plasmodium, remains one of the most dreadful infectious ... more Malaria, caused by protozoa of the genus Plasmodium, remains one of the most dreadful infectious diseases worldwide killing more than 1 million people per year. The emergence of multidrug-resistant parasites highly demands a steadfast and continuous search not only for new targets but also for new anti-infectives addressing the known ones. As proteases in general have been proven to be excellent drug targets and the development of inhibitors has frequently resulted in approved drugs, this review will only focus on the proteases of Plasmodium falciparum as drug targets. The completion of the sequencing of the Plasmodium falciparum genome in 2002 lead to the discovery of nearly 100 putative proteases encoded therein. Within this review, only those proteases and inhibitors thereof will be discussed in more detail, in which their biological function has been determined undoubtedly or in those cases, in which the development of specific inhibitors has significantly contributed to the understanding of the underlying biological role of the respective protease thus validating the role as promising drug target.
Current Topics in Medicinal Chemistry, 2010
ABSTRACT Members of the protease families discussed in this issue are of great interest for diffe... more ABSTRACT Members of the protease families discussed in this issue are of great interest for different therapeutic areas tackling contemporary afflictions of mankind such as cardiovascular, infective, or respiratory diseases as well as cancer. The proteases dealt with not only act as protein-degrading enzymes, their important function within signaling pathways makes them also highly attractive as valid drug targets. The search for as well as the identification of potent and selective inhibitors for this protein family has been very popular for decades and still is a highly competitive field in industrial and academic drug research development. This special issue of Current Topics in Medicinal Chemistry “The Medicinal Chemistry of Protease Inhibitors” focuses on inhibitors of different protease classes and is divided into three major parts: the first part discusses inhibitors for particular members of the threonine, serine, and cysteine protease family, the second gives an overview of proteases and their inhibitors involved in infectious diseases, and the third part reviews hit validation, conducting as well as pitfalls frequently occurring in protease assays. The issue starts with a review of Genin, Reboud-Ravaux, and Vidal on recent advances and new perspectives of proteasome inhibitors. The well-known covalent inhibitors for this member of the threonine protease family as well as recent developments towards first non-covalent derivatives are discussed. In the following, Straub, Rohrig, and Hillisch highlight the field of factor Xa, representing one example of the serine protease family, and its corresponding inhibitors. Their review concentrates on different non-basic P1-site inhibitors and describes in particular the development of Rivaroxaban (Xarelto™). The family of cysteine proteases and their inhibitors are presented within two contributions. Pietsch, Chua, and Abell introduce into the field of calpains as attractive drug targets and inhibitors thereof, followed by an article of Frizler, Stirnberg, Sisay, and Gütschow discussing nitrile-based peptidic inhibitors for the subfamily of cathepsins. The subsequent part of this issue focuses on proteases that are suitable drug targets to combat infectious diseases. The aim of this part is to give a survey of active compounds inhibiting proteases of different classes but share their quality of being active in only one therapeutic category. Steuber and Hilgenfeld describe the class of viral proteases which are investigated within the antiviral drug discovery. A second topic, summarized in a review of Wegscheid-Gerlach, Gerber and Diederich, deals with different malarial proteases of plasmodium falciparum and inhibitors thereof. In the final part of this issue, Ludewig, Kossner, Schiller, Baumann, and Schirmeister discuss in their contribution entitled “Enzyme kinetics and hit validation in fluorimetric protease assays” common problems frequently occurring in fluorimetric assays. They furthermore provide methods and strategies concerning problem solving as well as circumventive measures prior to assay determination. We very much appreciated the valuable contributions of all authors to this special issue of Current Topics in Medicinal Chemistry entitled “The Medicinal Chemistry of Protease Inhibitors”. We would also like to thank all reviewers for their very constructive comments. We are also grateful to the editor-in-chief, Dr. Allen Reitz, for the invitation and the opportunity to compile this special issue as guest editors and for all his support concerning the preparation of this special issue.
Fragment-based approaches have become very popular within the lead finding phase of a drug design... more Fragment-based approaches have become very popular within the lead finding phase of a drug design project. Different experimental techniques such as X-ray and NMR-supported protocols have been developed to detect and applied to successfully novel lead structures (1). In addition, in silico approaches considering either descriptor- (2), ligand- (3) or structure- based (4) information for navigating within chemical fragment spaces
Journal of Organometallic Chemistry, 2006
We have developed a short and highly efficient synthetic strategy towards the hitherto hardly kno... more We have developed a short and highly efficient synthetic strategy towards the hitherto hardly known 3,5-and 3,6-disubstituted 2,3,4,7tetrahydro-1H-azepine scaffold via a ring-closing metathesis approach utilizing inexpensive and readily available starting material such as methyl acrylate and allylamine. Both seven-membered azacycle scaffolds bearing suitable functional groups, which can easily be modified by means of standard synthetic chemistry, serve as non-peptidic heterocyclic core structures for the further design and synthesis of aspartic protease inhibitors. Through specific decoration with appropriate side chains, individual inhibitors can be tailored with respect to selectivity towards particular family members. A first generation of this class of non-peptidic inhibitors have been tested against the aspartic proteases Plasmepsin II and HIV-I protease, respectively, showing promising activity as well as selectivity with IC 50 values in the micromolar range.
Journal of Molecular Biology, 2006
In structure-based drug design, accurate crystal structure determination of protein-ligand comple... more In structure-based drug design, accurate crystal structure determination of protein-ligand complexes is of utmost importance in order to elucidate the binding characteristics of a putative lead to a given target. It is the starting point for further design hypotheses to predict novel leads with improved properties. Often, crystal structure determination is regarded as ultimate proof for ligand binding providing detailed insight into the specific binding mode of the ligand to the protein. This widely accepted practise relies on the assumption that the crystal structure of a given protein-ligand complex is unique and independent of the protocol applied to produce the crystals. We present two examples indicating that this assumption is not generally given, even though the composition of the mother liquid for crystallisation was kept unchanged: Multiple crystal structure determinations of aldose reductase complexes obtained under varying crystallisation protocols concerning soaking and crystallisation exposure times were performed resulting in a total of 17 complete data sets and ten refined crystal structures, eight in complex with zopolrestat and two complexed with tolrestat. In the first example, a flip of a peptide bond is observed, obviously depending on the crystallisation protocol with respect to soaking and co-crystallisation conditions. This peptide flip is accompanied by a rupture of an H-bond formed to the bound ligand zopolrestat. The indicated enhanced local mobility of the complex is in agreement with the results of molecular dynamics simulations. As a second example, the aldose reductase-tolrestat complex is studied. Unexpectedly, two structures could be obtained: one with one, and a second with four inhibitor molecules bound to the protein. They are located in and near the binding pocket facilitated by crystal packing effects. Accommodation of the four ligand molecules is accompanied by pronounced shifts concerning two helices interacting with the additional ligands.
Journal of Molecular Biology, 2009
The field of medicinal chemistry aims to design and optimize small molecule leads into drug candi... more The field of medicinal chemistry aims to design and optimize small molecule leads into drug candidates that may positively interfere with pathological disease situations in humans or combat the growth of infective pathogens. From the plethora of crystal structures of protein-inhibitor complexes we have learned how molecules recognize each other geometrically, but we still have rather superficial understanding of why they bind to each other. This contribution surveys a series of 26 thrombin inhibitors with small systematic structural differences to elucidate the rationale for their widely deviating binding affinity from 185 microM to 4 nM as recorded by enzyme kinetic measurements. Five well-resolved (resolution 2.30 - 1.47 A) crystal structures of thrombin-inhibitor complexes and an apo-structure of the uncomplexed enzyme (1.50 A) are correlated with thermodynamic data recorded by isothermal titration calorimetry with 12 selected inhibitors from the series. Taking solubility data into account, the variation in physicochemical properties allows conclusions to be reached about the relative importance of the enthalpic binding features as well as to estimate the importance of the parameters more difficult to capture, such as residual ligand entropy and desolvation properties. The collected data reveal a comprehensive picture of the thermodynamic signature that explains the so far poorly understood attractive force experienced by m-chloro-benzylamides to thrombin.
Journal of Computer-Aided Molecular Design, 2008
FTrees (FT) is a known chemoinformatic tool able to condense molecular descriptions into a graph ... more FTrees (FT) is a known chemoinformatic tool able to condense molecular descriptions into a graph object and to search for actives in large databases using graph similarity. The query graph is classically derived from a known active molecule, or a set of actives, for which a similar compound has to be found. Recently, FT similarity has been extended to fragment space, widening its capabilities. If a user were able to build a knowledge-based FT query from information other than a known active structure, the similarity search could be combined with other, normally separate, fields like de-novo design or pharmacophore searches. With this aim in mind, we performed a comprehensive analysis of several databases in terms of FT description and provide a basic statistical analysis of the FT spaces so far at hand. Vendors' catalogue collections and MDDR as a source of potential or known "actives", respectively, have been used. With the results reported herein, a set of ranges, mean values and standard deviations for several query parameters are presented in order to set a reference guide for the users. Applications on how to use this information in FT query building are also provided, using a newly built 3D-pharmacophore from 57 5HT-1F agonists and a published one which was used for virtual screening for tRNA-guanine transglycosylase (TGT) inhibitors.
Angewandte Chemie International Edition, 2007
Angewandte Chemie International Edition, 2007