Biomedical subjects

M Rarey

Publications and source records attributed to M Rarey.

6 recordsLinked to original sources

PubMed1997

CASP2 experiences with docking flexible ligands using FlexX.

We have applied our docking program FlexX to all eight CASP2 targets involving protein complexes with small ligands. Of the seven targets that were kept in the CASP2 experiment, we could solve two. We found important parts of the solution in four other examples, and were unsuccessful on the remaining example. This paper discusses all predictions in detail. Each of our prediction runs took just a few minutes of computer time on a standard workstation and could thus be demonstrated in real time at the CASP meeting. We believe that this speed is the prime strength of our program FlexX. In quality, our predictions are competitive with those produced by other predictors. The experiment showed that possible objectives of improvement of the FlexX program are to incorporate relevant aspects of receptor flexibility, deal with water molecules in the receptor pocket, allow for a postoptimization to refine favorable complexes, and improve the scoring function.

Amiloride↗

PubMed1997

Multiple automatic base selection: protein-ligand docking based on incremental construction without manual intervention.

A possible way of tackling the molecular docking problem arising in computer-aided drug design is the use of the incremental construction method. This method consists of three steps: the selection of a part of a molecule, a so-called base fragment, the placement of the base fragment into the active site of a protein, and the subsequent reconstruction of the complete drug molecule. Assuming that a part of a drug molecule is known, which is specific enough to be a good base fragment, the method is proven to be successful for a large set of docking examples. In addition, it leads to the fastest algorithms for flexible docking published so far. In most real-world applications of docking, large sets of ligands have to be tested for affinity to a given protein. Thus, manual selection of a base fragment is not practical. On the other hand, the selection of a base fragment is critical in that only few selections lead to a low-energy structure. We overcome this limitation by selecting a representative set of base fragments instead of a single one. In this paper, we present a set of rules and algorithms to automate this selection. In addition, we extend the incremental construction method to deal with multiple fragmentations of the drug molecule. Our results show that with multiple automated base selection, the quality of the docking predictions is almost as good as with one manually preselected base fragment. In addition, the set of solutions is more diverse and alternative binding modes with low scores are found. Although the run time of the overall algorithm increases, the method remains fast enough to search through large ligand data sets.

Automation↗

PubMed1996

A fast flexible docking method using an incremental construction algorithm.

We present an automatic method for docking organic ligands into protein binding sites. The method can be used in the design process of specific protein ligands. It combines an appropriate model of the physico-chemical properties of the docked molecules with efficient methods for sampling the conformational space of the ligand. If the ligand is flexible, it can adopt a large variety of different conformations. Each such minimum in conformational space presents a potential candidate for the conformation of the ligand in the complexed state. Our docking method samples the conformation space of the ligand on the basis of a discrete model and uses a tree-search technique for placing the ligand incrementally into the active site. For placing the first fragment of the ligand into the protein, we use hashing techniques adapted from computer vision. The incremental construction algorithm is based on a greedy strategy combined with efficient methods for overlap detection and for the search of new interactions. We present results on 19 complexes of which the binding geometry has been crystallographically determined. All considered ligands are docked in at most three minutes on a current workstation. The experimentally observed binding mode of the ligand is reproduced with 0.5 to 1.2 A rms deviation. It is almost always found among the highest-ranking conformations computed.

Algorithms↗

PubMed1996

Placement of medium-sized molecular fragments into active sites of proteins.

We present an algorithm for placing molecular fragments into the active site of a receptor. A molecular fragment is defined as a connected part of a molecule containing only complete ring systems. The algorithm is part of a docking tool, called FLEXX, which is currently under development at GMD. The overall goal is to provide means of automatically computing low-energy conformations of the ligand within the active site, with an accuracy approaching the limitations of experimental methods for resolving molecular structures and within a run time that allows for docking large sets of ligands. The methods by which we plan to achieve this goal are the explicit exploitation of molecular flexibility of the ligand and the incorporation of physicochemical properties of the molecules. The algorithm for fragment placement, which is the topic of this paper, is based on pattern recognition techniques and is able to predict a small set of possible positions of a molecular fragment with low flexibility within seconds on a workstation. In most cases, a placement with rms deviation below 1.0 A with respect to the X-ray structure is found among the 10 highest ranking solutions, assuming that the receptor is given in the bound conformation.

Algorithms↗

PubMed1996

Computational methods for biomolecular docking.

With the rapidly increasing amount of molecular biological data available, the computer-based analysis of molecular interactions becomes more and more feasible. Methods for computer-aided molecular docking have to include a reasonably accurate model of energy and must be able to deal with the combinatorial complexity incurred by the molecular flexibility of the docking partners. In both respects, recent years have seen substantial progress.

Databases, Factual↗

PubMed1995

Time-efficient docking of flexible ligands into active sites of proteins.

We present an algorithm for placing flexible molecules in active sites of proteins. The two major goals in the development of our docking program, called FLEXX, are the explicit exploitation of molecular flexibility of the ligand and the development of a model of the docking process that includes the physico-chemical properties of the molecules. The algorithm consists of three phases: The selection of a base fragment, the placement of the base fragment in the active site, and the incremental construction of the ligand inside the active site. Except for the selection of the base fragment, the algorithm runs without manual intervention. The algorithm is tested by reproducing 11 receptor-ligand complexes known from X-ray crystallography. In all cases, the algorithm predicts a placement of the ligand which is similar to the crystal structure (about 1.5 A RMS deviation or less) in a few minutes on a workstation, assuming that the receptor is given in the bound conformation.

Algorithms↗