David C. Spellmeyer

Conformational analysis using distance geometry methods

Distance geometry methods have been used extensively to build models of molecules of various sizes, including small molecules, peptides, and proteins. These methods are often overlooked as tools for conformational analysis, even though they often perform as well as other conformational sampling methods. We have implemented two new distance geometry approaches in the DGEOM95 package. In the first new method, the traditional embedding algorithm is replaced with a procedure that generates random 4D coordinates for each atom, followed by refinement of these coordinates into 3D using the distance geometry error function. The conformational sampling produced by this method is comparable to that obtained with partial metrization, and superior to that obtained with the original embedding procedure. In the second method, a molecular dynamics step is included in the refinement stage. Although this method can be applied to any embedding algorithm, substantial improvements in sampling are seen primarily with the original embedding algorithm.

Nmr Structural Characterization of Oligo-N-Substituted Glycine Lead Compounds from a Combinatorial Library

Synthesis and screening of combinatorial librariesfor pharmaceutical lead discovery is a rapidlyexpanding field. Oligo-N-substituted glycines (NSGs)were one of the earliest sources of moleculardiversity in combinatorial libraries. In one of thefirst demonstrations of the power of combinatorialchemistry, two NSG trimers, CHIR-2279 and CHIR-4531,were identified as nM ligands for two 7-transmembraneG-protein-coupled receptors. The NMR characterizationof these two lead compounds was undertaken to verifycovalent connectivity and to determine solutionconformations, if any. The sequential chemical shiftassignments were performed using a new strategy forassigning 1H and 13C resonances of NSGs. The conformational preferences were then determined inboth an aqueous co-solvent system and an organicsolvent to probe the effects of hydrophobic collapse. NSGs are expected to be more flexible than peptidesdue to the tertiary amide, with both cis andtrans amide bond conformations being accessible. Solution NMR studies indicate that although CHIR-2279and CHIR-4531 have identical backbones and termini,and very similar side chains, they do not display thesame solution conformational characteristics.

Endothelin receptor ligands. replacement net approach to SAR determination of potent hexapeptides

Abstract We determined the SAR of the potent hexapeptide endothelin ligand Ac-Dphe-Orn-Asp-Ile-Ile-Trp-OH1 (1) through the systematic replacement of each residue with 50 amino acid substitutes. Multipin peptide synthesis methods allowed us to rapidly synthesize and then screen all 300 analogues.

Chapter 7. Small Molecule Endothelin Receptor Antagonists

Publisher Summary Advances in molecular biology have led to the discovery of the endothelin(ET) family of peptides, their biological precursors, their receptors, and their processing enzymes. E receptor antagonists are useful in elucidating pathological effect and disease states, involving ET-1. The ET family of 21-amino acid peptides possesses an unusual chemical structure, containing two disulfide bonds. Two different ET converting enzymes (ECEs), such as metalloproteinase and aspartyl proteinase, are responsible for converting the biological precursor peptides to the biologically active ETs. Three unique receptor subtypes belongs to the seven-transmembrane G-protein coupled receptor superfamily. The ET A receptor subtype shows higher affinity for ET-1 and ET-2 than for ET-3 and is known to mediate vasoconstriction. The ET B receptor subtype binds ET-1, ET-2, and ET-3, with equal affinities, and also used to mediate both vasoconstriction and vasodilation. Elevated levels of ET-1 are found in many diseases, such as cardiovascular, respiratory, gastric, renal, and urological diseases. Natural product screening has produced peptides, depsipeptides, and small molecules. Both random screening and directed screening of chemical libraries have led to the discovery of several classes of small molecules. Chemical optimization of many of these leads has produced potent and bioavailable small molecule ET receptor antagonists. The development of bioavailable small molecule ET antagonists is useful in unraveling the role of ET in disease states and in elucidating that unmet medical needs might be treated with ET antagonists.

Endothelin eceptor Ligands. Multiple D-Amino acid replacement net approach

Abstract All possible single and multiple L- to D- amino acid replacements of a potent hexapeptide endothelin receptor ligand were synthesized and tested. While most of these 64 analogues were inactive on the ETRA receptor, three showed submicromolar activity. Interestingly, two of these contain 5D-amino acids and may be stable to proteolysis.

Synthesis, molecular modelling, and NMR structure determination of four cyclic peptide antagonists of endothelin

A combined distance geometry and molecular mechanics/dynamics (MM/MD) protocol was unable to predict the active conformation of the cyclic pentapeptide inhibitor of endothelin-1 receptor, BQ-123, and two analogues. However, the MM/MD method alone is sufficient to predict the solution conformation of a third analogue. In that one case, the combination of proline at residue 3 and an N alpha-methyl substitution at residue 5 provides enough internal constraints to eliminate conformational flexibility seen in the other three analogues. For this constrained analogue, the 50 lowest energy conformations (out of a set of 500 DGEOM-generated, MM/MD minimized conformations) differ by no more than 3.9 kcal/mol. Thirty three of these 50 conformations have backbone atom RMSDs of less than 0.33 A, relative to the lowest energy conformation. The accuracy of this MM/MD model is verified by determining the solution structure of each of the four analogues with 2D NMR techniques. Each of the cyclic pentapeptides has a well defined solution conformation where a proline residue is clearly in a gamma-turn, leaving the remaining residues in a loose beta-turn. All four experimental NMR conformations agree closely with the MM/MD model.

The effect of workstation technology on methods in drug design and discovery

The last two decades have seen the birth, emergence and acceptance of the field of computational drug design and discovery. In the early days of this period, computer-aided drug design was performed on mainframe or supercomputers by specialists. Modern-day workstations provide access to a large palette of powerful software tools to a wide audience of computational, medicinal and bioorganic chemists. In this paper we review the trends in computer hardware that have led to powerful computer systems, including the evolution of workstations from the microprocessors used in personal computers and the gradual development of workstation networks. We predict how advances in workstation technology will affect computational drug design and discovery in the future. We also outline some challenges that need to be faced to make workstation-based computational chemistry even more useful.