Markus Böhm

Philipps University of Marburg, Marburg, Hesse, Germany

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Publications (13)38.5 Total impact

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    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 12/2010; 32(50). DOI:10.1002/chin.200150187
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    ABSTRACT: A 3D QSAR selectivity analysis of carbonic anhydrase (CA) inhibitors using a data set of 87 CA inhibitors is reported. After ligand minimization in the binding pockets of CA I, CA II, and CA IV isoforms, selectivity CoMFA and CoMSIA 3D QSAR models have been derived by taking the affinity differences (DeltapKi) with respect to two CA isozymes as independent variables. Evaluation of the developed 3D QSAR selectivity models allows us to determine amino acids in the respective CA isozymes that possibly play a crucial role for selective inhibition of these isozymes. We further combined the ligand-based 3D QSAR models with the docking program AUTODOCK in order to screen for novel CA inhibitors. Correct binding modes are predicted for various CA inhibitors with respect to known crystal structures. Furthermore, in combination with the developed 3D QSAR models we could successfully estimate the affinity of CA inhibitors even in cases where the applied scoring function failed. This novel strategy to combine AUTODOCK poses with CoMFA/CoMSIA 3D QSAR models can be used as a guideline to assess the relevance of generated binding modes and to accurately predict the binding affinity of newly designed CA inhibitors that could play a crucial role in the treatment of pathologies such as tumors, obesity, or glaucoma.
    Journal of Chemical Information and Modeling 11/2006; 46(6):2737-60. DOI:10.1021/ci600298r · 3.74 Impact Factor
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    ABSTRACT: We recently described two novel aryl binding sites of farnesyltransferase. In this study, the cinnamoyl residue was designed as an appropriate substituent for our benzophenone-based AAX-peptidomimetic compound capable of occupying the far aryl binding site.
    Archiv der Pharmazie 09/2004; 337(9):493-501. DOI:10.1002/ardp.200400871 · 1.53 Impact Factor
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    ABSTRACT: We recently described two novel aryl binding sites of farnesyltransferase. The arylacetyl residue was designed as an appropriate substituent for our benzo-phenone-based AAX-peptidomimetic compound capable of occupying the near aryl binding site which is located next to the catalytic zinc ion. Non-thiol farnesyl-transferase inhibitors with micromolar to submicromolar activity were obtained.
    Archiv der Pharmazie 08/2004; 337(4):213-8. DOI:10.1002/ardp.200300843 · 1.53 Impact Factor
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    ABSTRACT: The molecular alignments obtained from a previously reported pharmacophore model have been employed in a three-dimensional quantitative structure-activity relationship (3D QSAR) study, to obtain a more detailed insight into the structure-activity relationships for D(2) and D(4) receptor antagonists. The frequently applied CoMFA method and the related CoMSIA method were used. Statistically significant models have been derived with these two methods, based on a set of 32 structurally diverse D(2) and D(4) receptor antagonists. The CoMSIA and the CoMFA methods produced equally good models expressed in terms of q(2) values. The predictive power of the derived models were demonstrated to be high. Graphical interpretation of the results, provided by the CoMSIA method, brings to light important structural features of the compounds related to either low- or high-affinity D(2) or D(4) antagonism. The results of the 3D QSAR studies indicate that bulky N-substituents decrease D(2) binding, whereas D(4) binding is enhanced. Electrostatically favorable and unfavorable regions exclusive to D(2) receptor binding were identified. Likewise, certain hydrogen-bond acceptors can be used to lower D(2) affinity. These observations may be exploited for the design of novel dopamine D(4) selective antagonists.
    Journal of Chemical Information and Computer Sciences 09/2003; 43(3):1020-7. DOI:10.1021/ci034004+
  • Markus Böhm · Gerhard Klebe ·
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    ABSTRACT: Knowledge-based descriptors extracted from composite crystal-field environments in crystal data have been developed for the description of interaction properties of small molecules. Using SuperStar seven diverse probe atoms have been selected to reflect the most important physicochemical properties. The general application of these descriptors in comparative molecular field analysis has been investigated using a dataset of thermolysin inhibitors, and a comparison to the GRID program has been performed. We especially focused on hydrogen-bond donor and acceptor properties by selecting a carbonyl and amino group as suitable probes. Their performance has been compared to that of the hydrogen-bond descriptors presently implemented in CoMSIA (comparative molecular similarity indices analysis). The newly developed descriptors produced significantly improved statistics for the correlation analyses if they are exclusively applied or, even better, applied in combination with other CoMSIA descriptors. Two methodologically different approaches have been tested to approximate the developed descriptors. Both reduce significantly the required computational efforts in particular for large data sets. The graphical interpretation of the field contributions of hydrogen-bonding properties elucidates additional features compared to those obtained from the original CoMSIA method. They are of valuable support for the design of improved inhibitors.
    Journal of Medicinal Chemistry 05/2002; 45(8):1585-97. DOI:10.1021/jm011039x · 5.45 Impact Factor
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    ABSTRACT: In the course of our studies on non-thiol farnesyltransferase inhibitors based on the 2, 5-diaminobenzophenone AAX-peptidomimetic substructure, we have developed the (4-nitrophenyl)butyryl (R(1)), the (2-naphthyl)acryloyl (R(2)), the 4-nitrocinnamoyl (R(3)), and the 5-(4-nitrophenyl)furylacryloyl (R(4)) groups as useful cysteine replacements. In this study, we combined these four groups with other AA(X)-peptidomimetic substructures (5-10: R = H) reported in the literature. The 5-(4-nitrophenyl)furylacryloyl moiety (R(4)) turned out to be the most useful non-thiol cysteine replacement yielding in all cases the most active inhibitors. By combination of this 5-(4-nitrophenyl) furylacryloyl moiety (R(4)) with the structurally simple AAX-peptidomimetics 4-aminobenzophenone (5) and 4-aminodiphenylsulfone (6) potent, readily accessible non-thiol farnesyltransferase inhibitors were obtained (IC(50) = 12 nMand 10 nM).
    Archiv der Pharmazie 04/2002; 335(4):135-42. DOI:10.1002/1521-4184(200204)335:4<135::AID-ARDP135>3.0.CO;2-7 · 1.53 Impact Factor
  • Martin Schlitzer · Markus Böhm · Isabel Sattler ·
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    ABSTRACT: Investigations on the structure-activity relationships of benzophenone-based bisubstrate analogue farnesyltransferase inhibitors yielded a bisubstrate analogue farnesyltransferase inhibitor lacking any prenylic or peptidic substructures with nanomolar activity. This represents a considerable progress in comparison to those non-prenylic, non-peptidic bisubstrate analogue farnesyltransferase inhibitors we have described before which utilized AAX-peptidomimetic substructures different from the benzophenone since those inhibitors displayed activity only in the micromolar range.
    Bioorganic & Medicinal Chemistry 04/2002; 10(3):615-20. DOI:10.1016/S0968-0896(01)00312-1 · 2.79 Impact Factor
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    ABSTRACT: Most non-thiol CAAX-peptidomimetic farnesyltransferase inhibitors bear nitrogen-containing heterocycles in place of the terminal cysteine which are supposed to coordinate the enzyme-bound zinc. However, it has been shown that those nitrogen-containing heterocycles can be replaced by carbocyclic aromatic moieties which are unable to coordinate the zinc ion, a conclusion that resulted in the postulation of one or two hitherto unknown aryl binding sites. No indication has been given about the spatial location of these novel binding sites. Employing flexible docking of several non-thiol farnesyltransferase inhibitors known from the literature and some model compounds based on our benzophenone scaffold as well as performing GRID searches, we have identified two regions in the farnesyltransferase's active site which we suggest being the postulated aryl binding sites. One aryl binding region is located in close proximity to the zinc ion and is defined by the aromatic side chains of Tyr 300beta, Trp 303beta, Tyr 361beta, and Tyr 365beta. The second aryl binding site is defined by the side chains of Tyr 300beta, Leu 295beta, Lys 294beta, Lys 353beta, and Lys 356beta. This second aryl binding site has been used for the design of a non-thiol farnesyltransferase inhibitor (9c) with an IC(50) of 35 nM.
    Journal of Medicinal Chemistry 10/2001; 44(19):3117-24. DOI:10.1021/jm010873j · 5.45 Impact Factor
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    ABSTRACT: Because of the involvement of farnesylated proteins in oncogenesis, inhibition of the protein-modifying enzyme farnesyltransferase is considered a major emerging strategy in cancer therapy. Here, we describe the structure-activity relationship of a novel class of CAAX-peptidomimetic farnesyltransferase inhibitors based on the benzophenone scaffold. 4'-Methyl, 4'-chloro, 4'-bromo, and 4'-nitrophenylacetic acid as substituents at the 2-amino group of the benzophenone core structure yield farnesyltransferase inhibitors active in the nanomolar range. Using diphenylacetic acid in this position further improves activity. SEAL superimposition of inhibitor 12a to the enzyme-bound conformation of a CAAX-peptide shows a markedly good resemblance of the molecular properties of the peptide. FlexX docking of 12a confirms the good fit of the molecule into the peptide binding site of farnesyltransferase. The novel benzophenone-based AAX-peptidomimetic substructure described here will be useful for the design of some novel types of farnesyltransferase inhibitors.
    Journal of Medicinal Chemistry 09/2001; 44(18):2886-99. DOI:10.1021/jm010872r · 5.45 Impact Factor
  • Source
    Martin Schlitzer · Markus Böhm · Isabel Sattler ·
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    ABSTRACT: Recently, we have described non-peptidic, non-prenylic bisubstrate analogues as a novel type of farnesyltransferase inhibitor composed of a farnesyl-mimetic, a linker and an AAX-peptidomimetic substructure. With this study, we showed that the amide function connecting the farnesyl-mimetic and the linking substructures of our inhibitors is crucial for their activity. We suggest that the amide is bound to the essential zinc ion in the farnesyltransferases active center. We identified succinic and glutaric acid, respectively, in addition to the initially used 1-alanyl moiety as suitable linking structures. Glycine can also be used in this function provided the distance between the alpha-amide group and the center of the peptidomimetic substructure is enlarged by introduction of an additional methylene unit into the peptidomimetic substructure.
    Bioorganic & Medicinal Chemistry 11/2000; 8(10):2399-406. DOI:10.1016/S0968-0896(00)00173-5 · 2.79 Impact Factor
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    Martin Schlitzer · Markus Böhm · Isabel Sattler · H M Dahse ·
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    ABSTRACT: Inhibition of the farnesylation of ras proteins has been identified as a promising target in tumor therapy. Only a few farnesyltransferase inhibitors are bisubstrate analogues displaying features of both substrates, the farnesylpyrophosphate and the C-terminal CAAX-tetrapeptide sequence of the ras protein. These known bisubstrate analogues consist of an AAX-tripeptide and a farnesyl residue connected through various linkers. We have developed a class of novel compounds that mimic a bisubstrate inhibitor structure and that differ from the known ones by lacking peptidic or farnesylic substructures. Long chain fatty acids and aryl-substituted carboxylic acids were used as farnesyl surrogates. These structures were linked to isoleucine amide, benzoic acid amide, N-substituted aminobenzenesulfonamides and N(alpha)-aryl-substituted methionine derivatives, respectively, which function as AA- or AAX-mimetics.
    Bioorganic & Medicinal Chemistry 09/2000; 8(8):1991-2006. DOI:10.1016/S0968-0896(00)00138-3 · 2.79 Impact Factor
  • Markus Böhm · J St rzebecher · Gerhard Klebe ·
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    ABSTRACT: Three-dimensional quantitative structure-activity relationship (3D QSAR) methods were applied using a training set of 72 inhibitors of the benzamidine type with respect to their binding affinities (Ki values) toward thrombin, trypsin, and factor Xa to yield statistically reliable models of good predictive power. Two methods were compared: the widely used comparative molecular field analysis (CoMFA) and the recently reported CoMSIA approach (comparative molecular similarity indices analysis). CoMSIA produced significantly better results for all correlations. Furthermore, in contrast to CoMFA, CoMSIA is not sensitive to changes in orientation of the superimposed molecules in the lattice. The correlation results obtained by CoMSIA were graphically interpreted in terms of field contribution maps allowing physicochemical properties relevant for binding to be easily mapped back onto molecular structures. The advantage of this feature is demonstrated using the maps to design new molecules. Finally, the CoMSIA method was applied to elucidate structural features among ligands which are responsible for affinity differences toward thrombin and trypsin. These selectivity-determining features were interpreted graphically in terms of spatial regions responsible for affinity discrimination. Such indicators are highly informative for the lead optimization process with respect to selectivity enhancement.
    Journal of Medicinal Chemistry 03/1999; 42(3):458-77. DOI:10.1021/jm981062r · 5.45 Impact Factor