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Biomedical subjects

A Peter Johnson

Publications and source records attributed to A Peter Johnson.

7 recordsLinked to original sources
PubMed2007

Design and synthesis of potent inhibitors of the malaria parasite dihydroorotate dehydrogenase.

Pyrimidine biosynthesis presents an attractive drug target in malaria parasites due to the absence of a pyrimidine salvage pathway. A set of compounds designed to inhibit the Plasmodium falciparum pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (PfDHODH) was synthesized. PfDHODH-specific inhibitors with low nanomolar binding affinities were identified that bind in the N-terminal hydrophobic channel of dihydroorotate dehydrogenase, the presumed site of ubiquinone binding during oxidation of dihydroorotate to orotate. These compounds also prevented growth of cultured parasites at low micromolar concentrations. Models that suggest the mode of inhibitor binding is based on shape complementarity, matching hydrophobic regions of inhibitor and enzyme, and interaction of inhibitors with amino acid residues F188, H185, and R265 are supported by mutagenesis data. These results further highlight PfDHODH as a promising new target for chemotherapeutic intervention in prevention of malaria and provide better understanding of the factors that determine specificity over human dihydroorotate dehydrogenase.

Aminobiphenyl Compounds↗
PubMed2006

Molecular complexity analysis of de novo designed ligands.

The de novo approach to structure-based rational drug design can provide a powerful tool for suggestion of entirely novel potential leads. However, programs for structure generation typically generate large numbers of putative ligands; therefore, various heuristics (such as estimation of binding affinity and synthetic accessibility) have to be adopted to evaluate and prune large answer sets with the goal of suggesting ligands with high binding affinity but low structural complexity. A novel method for complexity analysis is described. This method provides a rapid and effective ranking technique for elimination of structures with complicated molecular motifs. This complexity analysis technique, implemented within the SPROUT de novo design system, is based on the statistical distribution of various cyclic and acyclic topologies and atom substitution patterns in existing drugs or commercially available starting materials. A novel feature of the technique that distinguishes it from other published methods is that the matching takes place at various levels of abstraction, so that it can evaluate complexity scores, even for structures which contain atoms with unspecified atom type, which is sometimes the case with the initial output of de novo structure generation systems.

Binding Sites↗
PubMed2006

eHiTS: a new fast, exhaustive flexible ligand docking system.

The flexible ligand docking problem is divided into two subproblems: pose/conformation search and scoring function. For successful virtual screening the search algorithm must be fast and able to find the optimal binding pose and conformation of the ligand. Statistical analysis of experimental data of bound ligand conformations is presented with conclusions about the sampling requirements for docking algorithms. eHiTS is an exhaustive flexible-docking method that systematically covers the part of the conformational and positional search space that avoids severe steric clashes, producing highly accurate docking poses at a speed practical for virtual high-throughput screening. The customizable scoring function of eHiTS combines novel terms (based on local surface point contact evaluation) with traditional empirical and statistical approaches. Validation results of eHiTS are presented and compared to three other docking software on a set of 91 PDB structures that are common to the validation sets published for the other programs.

Algorithms↗
PubMed2006

eHiTS: an innovative approach to the docking and scoring function problems.

Virtual Ligand Screening (VLS) has become an integral part of the drug design process for many pharmaceutical companies. In protein structure based VLS the aim is to find a ligand that has a high binding affinity to the target receptor whose 3D structure is known. This review will describe the docking tool eHiTS. eHiTS is an exhaustive and systematic docking tool which contains many automated features that simplify the drug design workflow. A description of the unique docking algorithm and novel approach to scoring used within eHiTS is presented. In addition a validation study is presented that demonstrates the accuracy and wide applicability of eHiTS in re-docking bound ligands into their receptors.

Algorithms↗
PubMed2003

Macrocyclic inhibitors of the bacterial cell wall biosynthesis enzyme MurD.

Computer-based molecular design has been used to produce a series of new macrocyclic systems targeted against the bacterial cell wall biosynthetic enzyme MurD. Following their preparation, which involved a novel metathesis-based cyclisation as the key step, these systems were found to show good inhibition when assayed against the MurD enzyme.

Binding Sites↗