Joseph B. Moon

3D database searching and de novo construction methods in molecular design

Abstract Computer-based lead finding algorithms which attempt to design, on a de novo basis, ligands that will complement a known receptor site cavity face some major problems in terms of a combinatorial design space and the synthesizability of the designed molecules. On the other hand, typical 3D database search methods provide a different set of challenges. Both of these approaches are ultimately pointed toward the same goal and can be used together productively. In this article we describe advances in both areas: we first describe extensions to our de novo ligand design software which combines (a) a tree-based conformational search over a library of fragments, and (b) a form of simulated annealing which allows designed ligands to crawl around the binding site even as their structures are changing. In the second part, we then discuss an implementation of the database approach which allows users to formulate 3D substructure, superstructure, or similarity queries based upon demonstrated or hypothetical requirements for activity. Finally, we draw the two approaches together with an example of current research interest, showing how one method can feed the other.

A fast algorithm for generating smooth molecular dot surface representations

The smooth molecular surface originally described by Richards and later implemented by Connolly in his MS program has become an important visualization technique in the field of molecular modeling. We describe here a new algorithm, called USURF, which approximates the MS dot surface, but with a twofold to sixfold enhancement of speed. The algorithm has been incorporated into our interactive modeling system, Mosaic, and is also available as a stand-alone program.

Design, synthesis, and biological evaluation of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, a potent, orally active, brain penetrant inhibitor of phosphodiesterase 5 (PDE5).

We recently described a novel series of aminopyridopyrazinones as PDE5 inhibitors. Efforts toward optimization of this series culminated in the identification of 3-[4-(2-hydroxyethyl)piperazin-1-yl]-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one, which possessed an excellent potency and selectivity profile and demonstrated robust in vivo blood pressure lowering in a spontaneously hypertensive rat (SHR) model. Furthermore, this compound is brain penetrant and will be a useful agent for evaluating the therapeutic potential of central inhibition of PDE5. This compound has recently entered clinical trials.

Peptidomimetic inhibitors of human immunodeficiency virus protease (HIV-PR): Design, enzyme binding and selectivity, antiviral efficacy, and cell permeability properties

Abstract The structure-activity relationships and pharmacophore modeling aspects of a series of HIV PR inhibitors modified at the N- and/or C-terminus of the dipeptide isostere ChaΨ[CH(OH)CH2]Val (Cha, cyclohexylalanine) are reported. The HIV PR binding affinity-selectivity (vs. human renin, pepsin, and cathepsins-D and E), antiviral efficacy (HIV-1/vVK-1 infected CV-1 cells) and cellular permeabilities (Caco-2) are noted.

Computer Modeling of Constrained Peptide Systems

Three approaches are described for dealing with conformational problems in constrained peptide systems. The first approach addresses the problem of de novo design of peptides where the structure of the binding or active site of the target protein is known. The method is based on a procedure, called GROW, which links together amino acid fragments from a library of amino acid conformations such that an “optimum fit” and solvation energy for the ligand are obtained. The second approach addresses the problem of modeling the surface loops of proteins. It is based upon the novel use of simulated annealing within the framework of a “random-tweak” type procedure [Shenkin et al., Proteins, 1989]. The method has been tested on 6- and 8-residue loops, and yields results that agree well with experiment at relatively little computational cost. The third approach addresses both cyclic peptides and surface-loop modeling using a mass-weighted molecular dynamics (MWMD) procedure. It is shown that MWMD is clearly superior to normal-mass MD sampling at equivalent temperatures, and is numerically stable. Moreover, the sampling of individual torsional degrees of freedom is also seen to be essentially complete for the case studied here, viz. for pressinoic acid, a cyclic hexapeptide derived from vasopressin.

Predicting the Three-Dimensional Structure of Proteins by Homology-Based Model Building

A priori prediction of the 3-D structure of proteins remains an important unsolved problem. Of the theoretical methods employed today, only homology-based model building produces protein structures of sufficient accuracy to be of use in structure-function and related studies. The present work provides a discussion of the features of protein structure which bear on homology-based model building in addition to a detailed description of the homology-based approach, with examples drawn from our own work.