Structure-based approaches in modern drug discovery research.
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Animals↗
Biomedical subjects
H J Böhm
Publications and source records attributed to H J Böhm.
Structure-based library design: molecular modelling merges with combinatorial chemistry.
Recent advances in both computational and experimental techniques now allow a very fruitful interplay of computational and combinatorial chemistry in the structure-based design of combinatorial libraries.
Combinatorial Chemistry Techniques↗
Combinatorial docking and combinatorial chemistry: design of potent non-peptide thrombin inhibitors.
A computational algorithm was used to design automatically novel thrombin inhibitors that are available from a single-step chemical reaction. The compounds do not contain amide bonds, are achiral and have a molecular weight below 400. Of the 10 compounds that were synthesized, five bind to thrombin with a Ki in the nanomolar range. Subsequent X-ray structure determination of the thrombin-inhibitor complex for the best compound (Ki = 95 nM) confirms the predicted binding mode. The novel algorithm is applicable to a broad range of chemical reactions.
Algorithms↗
Development of filter functions for protein-ligand docking.
Current docking methods can generate bound conformations of a ligand close to the experimentally observed structure of a protein-ligand complex. However, the scoring functions used to evaluate the potential solutions are not yet reliable enough at giving the highest ranks to the best structure predictions. One approach to this problem is the use of filter functions that are applied to all docked conformations to remove structures with certain energetically unfavorable properties. We present a computationally efficient scheme for such a postprocessing of docking results. For each of the conformations generated for a given protein-ligand complex, four properties are calculated: the fraction of the ligand volume buried inside the binding pocket, the size of lipophilic cavities along the protein-ligand interface, the solvent-accessible surface (SAS) of nonpolar parts of the ligand, and the number of close contacts between nonhydrogen-bonded polar atoms of the ligand and the protein. These four terms were used to filter out the majority of the calculated solutions and to rescore the remaining ones. On a test set of 32 protein-ligand complexes, this protocol significantly improves the accuracy of the structure predictions.
Crystallography, X-Ray↗
Prediction of binding constants of protein ligands: a fast method for the prioritization of hits obtained from de novo design or 3D database search programs.
A dataset of 82 protein-ligand complexes of known 3D structure and binding constant Ki was analysed to elucidate the important factors that determine the strength of protein-ligand interactions. The following parameters were investigated: the number and geometry of hydrogen bonds and ionic interactions between the protein and the ligand, the size of the lipophilic contact surface, the flexibility of the ligand, the electrostatic potential in the binding site, water molecules in the binding site, cavities along the protein-ligand interface and specific interactions between aromatic rings. Based on these parameters, a new empirical scoring function is presented that estimates the free energy of binding for a protein-ligand complex of known 3D structure. The function distinguishes between buried and solvent accessible hydrogen bonds. It tolerates deviations in the hydrogen bond geometry of up to 0.25 A in the length and up to 30 degrees in the hydrogen bond angle without penalizing the score. The new energy function reproduces the binding constants (ranging from 3.7 x 10(-2) M to 1 x 10(-14) M, corresponding to binding energies between -8 and -80 kJ/mol) of the dataset with a standard deviation of 7.3 kJ/mol corresponding to 1.3 orders of magnitude in binding affinity. The function can be evaluated very fast and is therefore also suitable for the application in a 3D database search or de novo ligand design program such as LUDI. The physical significance of the individual contributions is discussed.
Binding Sites↗
Discovery and optimization of a novel class of orally active nonpeptidic endothelin-A receptor antagonists.
A novel class of endothelin-A receptor ligands was discovered by high-throughput screening. Lead structure optimization led to highly potent antagonists which can be synthesized in a short sequence. The compounds are endothelin-A-selective, are orally available, and show a long duration of action.
Administration, Oral↗
Towards the automatic design of synthetically accessible protein ligands: peptides, amides and peptidomimetics.
The computer program LUDI for the de novo design of protein ligands was extended so that it is now able to take into account the synthetic accessibility of the constructed molecules. As an example, the design of peptides, amides and peptidomimetics using amino acids as building blocks is described. Two new libraries containing natural and non-natural amino acids were constructed for this purpose. Conformational flexibility is taken into account by using multiple conformers for each amino acid. The program was applied to the design of ligands for the enzymes elastase, renin and thermolysin.
Amides↗
Computational tools for structure-based ligand design.
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Binding Sites↗
Current computational tools for de novo ligand design.
Several new algorithms have been proposed recently for computational de novo ligand design. Empirical scoring functions are now available to prioritize the suggested structures. The first successful applications have been reported.
Algorithms↗
Design, synthesis and biological activity of novel rigid amidino-phenylalanine derivatives as inhibitors of thrombin.
(3S)-(Naphthalene-2-sulfonylamino)-1-[2R-(4-amidinophenyl)-1- piperidinocarbonylethyl]-2-pyrrolidinone (1a) is a potent inhibitor of thrombin with an IC50 value by 112 times lower than that of NAPAP (racemate). The selectivity versus trypsin can be improved by incorporation of substituents on the naphthyl ring. The mode of binding of the compound was determined by X-ray crystallography.
Animals↗
[Dynamic skin suture for secondary skin closure and treatment of skin defects].
Dynamic skin suture exerts progressive traction to the wound margins which allows a stepwise closure of a defect. It consists of interrupted sutures with two additional plastic tubes lying parallel to the wound margins on the surface of the skin. The extracuticular slopes of the sutures and the knots pass over these tubes. This decreases local pressure on the skin. The knots are performed in a way that, once they have been tied, permits further tightening without opening them. A viscoelastic property of the skin--stress-relaxation- reduces the tension on the sutures over time and allows a further tightening. As an example for the use of this technique, the results of closures of fasciotomies in compartment syndromes are presented. In 1993, 50 fasciotomies in 35 patients were treated with dynamic suture. In 42 defects (84%) a complete obliteration was possible. In the residual 8 defects reduction of size was significant. The mean time until obliteration was 11.5 days, in average sutures were tightened 4 times. The results suggest that dynamic suture is a useful technique for repair in fasciotomies. It helps avoiding tissue transplantations. The operative procedure itself is speedy and simple. Possible indications in limited excisional defects are demonstrated in a case report.
Adolescent↗
On the use of LUDI to search the Fine Chemicals Directory for ligands of proteins of known three-dimensional structure.
It is shown that the computer program LUDI can be used to search large database of three-dimensional structures for putative ligands of proteins with known 3D structure. As an example, a subset of approximately 30,000 small molecules (with less than 40 atoms and 0-2 rotatable bonds) from the Fine Chemicals Directory has been used in the search for possible novel ligands for four different proteins (trypsin, streptavidin, purine nucleoside phosphorylase and HIV protease). For trypsin and streptavidin, known ligands or substructures of known ligands are retrieved as top-scoring hits. In addition, a number of new interesting structures are found in all considered cases. Therefore, the method holds promise to retrieve automatically protein ligands from a 3D database if the 3D structure of the target protein is known.
Bacterial Proteins↗
The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure.
A new simple empirical function has been developed that estimates the free energy of binding for a given protein-ligand complex of known 3D structure. The function takes into account hydrogen bonds, ionic interactions, the lipophilic protein-ligand contact surface and the number of rotatable bonds in the ligand. The dataset for the calibration of the function consists of 45 protein-ligand complexes. The new energy function reproduces the binding constants (ranging from 2.5.10(-2) to 4.10(-14) M, corresponding to binding energies between -9 and -76 kJ/mol) of the dataset with a standard deviation of 7.9 kJ/mol, corresponding to 1.4 orders of magnitude in binding affinity. The individual contributions to protein-ligand binding obtained from the scoring function are: ideal neutral hydrogen bond: -4.7 kJ/mol; ideal ionic interaction: -8.3 kJ/mol; lipophilic contact: -0.17 kJ/mol A2; one rotatable bond in the ligand: +1.4 kJ/mol. The function also contains a constant contribution (+5.4 kJ/mol) which may be rationalized as loss of translational and rotational entropy. The function can be evaluated very fast and is therefore also suitable for application in a 3D database search or de novo ligand design program such as LUDI.
Binding Sites↗
[Dynamic skin suture for closure of the incision defect after compartment incision].
Dynamic skin suture consists of a technique that diminishes local pressure on skin and permits progressive tightening of the sutures for stepwise incisional closure. A clinical series of 28 repairs after release of compartment syndromes shows complete closure in 22 incisions, the other 6 defects could be reduced in size. Technique, results and biological basics are discussed.
Adolescent↗
A novel computational tool for automated structure-based drug design.
The computer program LUDI for automated structure-based drug design is described. The program constructs possible new ligands for a given protein of known three-dimensional structure. This novel approach is based upon rules about energetically favourable non-bonded contact geometries between functional groups of the protein and the ligand which are derived from a statistical analysis of crystal packings of organic molecules. In a first step small fragments are docked into the protein binding site in such a way that hydrogen bonds and ionic interactions can be formed with the protein and hydrophobic pockets are filled with lipophilic groups of the ligand. The program can then append further fragments onto a previously positioned fragment or onto an already existing ligand (e.g., a lead structure that one seeks to improve). It is also possible to link several fragments together by bridge fragments to form a complete molecule. All putative ligands retrieved or constructed by LUDI are scored. We use a simple scoring function that was fitted to experimentally determined binding constants of protein-ligand complexes. LUDI is a very fast program with typical execution times of 1-5 min on a work station and is therefore suitable for interactive usage.
Animals↗
[Aneurysmal bone cyst of the petrous bone. A rare cause of recurrent bacterial meningitis].
Occult malformations of the skull base are very rare disorders which cannot initially be diagnosed clinically. They become first symptomatic, if complications arise. The most frequent clinical manifestation is a recurrent bacterial meningitis. Based on the unique case of a presumably congenital aneurysmal bone cyst of the petrosal bone, which imposed clinically as hearing loss and recurrent bacterial meningitis, we have evaluated the extensive literature on this theme. Considering mostly atypical clinical findings, solely coronal thin-section computed tomographic scans of the skull base allow a reliable diagnosis. The possible risks of this investigation (necessary sedation up to insufflation anesthesia and the radiation exposure of the child's lens) are justifiable and subordinate to the diagnostic importance.
Adolescent↗