Prediction of Non‐bonded Interactions in Drug Design

Böhm, Hans‐Joachim

doi:10.1002/3527601813.ch1

Cited by 17 publications

(13 citation statements)

References 64 publications

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“…In the preceding section, we observed that all ligands have large binding energies. According to the lock‐and‐key paradigm, tight protein–ligand binding requires46 (a) high steric complementarity between the protein and the ligand, (b) high complementarity of the surface properties between the protein and the ligand, and (c) energetically favorable conformation of the ligand in the binding pocket. The paradigm is a useful basis to understand and predict binding between a protein and a ligand.…”

Section: Resultsmentioning

confidence: 99%

Molecular recognition mechanism of FK506 binding protein: An all‐electron fragment molecular orbital study

2007

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The fragment molecular orbital (FMO) method has enabled electronic structure calculations and geometry optimizations of very large molecules with ab initio quality. We applied the method to four FK506 binding protein (FKBP) complexes (denoted by their PDB codes 1fkb, 1fkf, 1fkg, and 1fki) containing rapamycin, FK506, and two synthetic ligands. The geometries of reduced complex models were optimized at the restricted Hartree-Fock (FMO-RHF) level using the 3-21G basis set, and then for a better estimate of binding, the energetics were refined at a higher level of theory (2nd order Møller-Plesset perturbation theory FMO-MP2 with the 6-31G* basis set). Thus, obtained binding energies were -103.9 (-82.0), -102.2 (-69.2), -70.1 (-57.7), and -71.3 (-55.3) kcal/mol for 1fkb, 1fkf, 1fkg, and 1fki, respectively, where the correlation contribution is given in parentheses. The results show that the electron correlation contribution to binding is extremely important, and it accounts for 70-80% of the binding energy. The molecular recognition mechanism of FKBP was analyzed in detail based on the FMO-pair interactions between protein residues and the ligands. Solvation effects on the protein-ligand binding were estimated using the Poisson-Boltzmann/surface area model.

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Section: Resultsmentioning

confidence: 99%

Molecular recognition mechanism of FK506 binding protein: An all‐electron fragment molecular orbital study

2007

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“…B. 80 [130] oder sogar 170 [135] Die Additivität einzelner Wechselwirkungen [138] hat sich schon früh bei quantitativen Struktur-Eigenschafts-Beziehungen (QSPR, quantitative structure-property relations) gezeigt; [139] bei Wechselwirkungen mit Wirt-Gast-Komplexen und mit biologischen Systemen spricht man dabei eher von QSAR (quantitative structure-activity relations). [140] In der Regel verwendet man einen möglichst großen Satz von experimentellen Daten als Trainingsdatensatz, unter Umstän-den unterstützt durch neue Methoden des Data-Mining.…”

Section: Quantifizierung Von Bindungsbeiträgen In Lösungunclassified

“…[129] Analysen von über 70 Proteinkomplexen ergaben ebenfalls DDG-Werte von etwa 5 kJ mol À1 . [130] 3.4. LFER-und QSPR/QSAR-Verfahren, Analysen bei Proteinkomplexen…”

Section: Messungen An Molekülen Mit Mutierten Bindungszentrenunclassified

Bindungsmechanismen in supramolekularen Komplexen

Schneider

2009

Angewandte Chemie

185

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Kräfte‐Sammelsurium: Supramolekulare Komplexe, wie der gezeigte, beruhen meist auf einer Kombination unterschiedlichster Wechselwirkungen, wie Ionenpaarbildung, Wasserstoffbrücken und Stapelwechselwirkungen. Die nicht immer einfache Charakterisierung von Natur und Stärke der intermolekularen Kräfte liefert Beiträge zum Verständnis biomimetischer Systeme wie auch zum Design von synthetischen Rezeptoren, Wirkstoffen und intelligenten Materialien. Die supramolekulare Chemie hat in den letzten Jahren eine enorme Ausdehnung erfahren, sowohl mit Blick auf mögliche Anwendungen wie auch auf analoge biologische Systeme. Bildung und Funktion supramolekularer Komplexe werden durch eine Vielzahl von oft schwer zu differenzierenden nichtkovalenten Kräften bestimmt. Ziel dieses Aufsatzes ist es, die entscheidenden Wechselwirkungsmechanismen zusammenhängend darzustellen und das Gesamtgebiet auf diese Weise zu klassifizieren. Als Beispiele werden meist organische Wirt‐Gast‐Komplexe gewählt, unter Berücksichtigung auch von biologisch relevanten Fragestellungen. Das Verständnis und die Quantifizierung der intermolekularen Wechselwirkungen ist für die rationale Planung neuer supramolekularer Systeme, einschließlich intelligenter Materialien, ebenso von Bedeutung wie für die Entwicklung neuer Wirkstoffe.

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“…[37][38][39] Although there may be a correlation between the higher hydrophobicity of AHTC relative to other TC derivatives 16,17) and the higher affinity, further contributions such as electrostatic forces should be considered. [40][41][42] Indeed, the relevance of electrostatic interaction in TC binding to BSA has been discussed previously. 31) Thus, the species distribution profile as a function of pH (Fig.…”

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confidence: 99%

Binding of the Highly Toxic Tetracycline Derivative, Anhydrotetracycline, to Bovine Serum Albumin

Burgos

Fernández

Celej

et al. 2011

Biological & Pharmaceutical Bulletin

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Tetracycline (TC) derivatives comprise a group of bacteriostatic antibiotics extensively used in human and veterinary medicine and in acquaculture, and as animal growth promoters due to their safe toxicological profile.1) More recently, they have been proposed as anti-amyloidogenic drugs since they can interfere with protein conformational changes and self-assemblies associated with protein misfolding and deposition diseases. 2-4)Despite their popular use, TC derivatives are highly unstable and some degradation products formed during the storage or normal use of the drugs are pharmacologically toxic or inactive compounds.5) Anhydrotetracycline (AHTC) is one of the major degradation products of TC that has been linked to several side effects of the drug, e.g., cutaneous phototoxicity 6) and Fanconi-type syndrome. 7) AHTC has also proven to be more toxic than TC against environmentally relevant bacteria. 8)AHTC can be produced by dehydration in acid media, 5,8) by photolysis in mild reducing conditions 6,9,10) or during high-temperature treatments.11) Removal of a water molecule from the C5a-C6 positions of TC by treatment with warm mineral acid gives the anhydroderivative (Fig. 1).12) Dehydration leads to significant changes in aromatization and planarity of the tetracyclic moiety, 13,14) showing variations in potency, 15) mechanism of action 1) and lipophilicity 16,17) as compared to the parent compound. Changes in chemical configuration can also modulate the interaction of drugs with serum proteins. 18)Serum albumins are the main carriers of physiological metabolites and pharmacological drugs in blood. Protein binding has a significant impact on the pharmacokinetics and biological activity of drugs and modulates the toxicity of bound substances, attenuates adverse reactions and prolongs the in vivo half-life of therapeutic agents. 18-21)The facts outlined above prompted us to investigate the interaction of AHTC with bovine serum albumin (BSA) using three biophysical techniques. Binding affinity and number of interacting ligands were assessed by fluorimetric titration. . Drug binding was enthalpically and entropically driven and seemed to involve hydrophobic interactions. AHTC fluorescence enhancement and hypsochromic shifts observed upon binding suggested a low-polarity location excluded from water for the bound drug. Our data are useful for evaluating the biodisponibility of the pharmacophore and the dynamic distribution of the toxic derivative.

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Prediction of Non‐bonded Interactions in Drug Design

Cited by 17 publications

References 64 publications

Molecular recognition mechanism of FK506 binding protein: An all‐electron fragment molecular orbital study

Molecular recognition mechanism of FK506 binding protein: An all‐electron fragment molecular orbital study

Bindungsmechanismen in supramolekularen Komplexen

Binding of the Highly Toxic Tetracycline Derivative, Anhydrotetracycline, to Bovine Serum Albumin

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