Development and screening of a polyketide virtual library for drug leads against a motilide pharmacophore

• Published in: Journal of molecular graphics & modelling 2000-08, Vol.18 (4-5), p.497-511
• Main Authors: Siani, Michael A, Skillman, A.Geoffrey, Carreras, Christopher W, Ashley, Gary, Kuntz, Irwin D, Santi, Daniel V
• Format: Article
• Language: English
• Subjects: Combinatorial Chemistry Techniques; Combinatorial mathematics; Computer Graphics; Computer Simulation; Computer systems programming; Conformations; Constraint theory; Database systems; Drug Design; Drug Evaluation, Preclinical; Drug products; Erythromycin - analogs & derivatives; Erythromycin - chemistry; Erythromycin - pharmacology; macrolactone; Models, Chemical; Models, Molecular; Molecular Conformation; motilide; pharmacophores; polyketide; Receptors, Gastrointestinal Hormone - agonists; Receptors, Neuropeptide - agonists; Software Design; Structure-Activity Relationship; virtual library; virtual screening
• ISSN: 1093-3263; 1873-4243
• DOI: 10.1016/S1093-3263(00)00070-X

A virtual library of macrocyclic polyketide molecules was generated and screened to identify novel, conformationally constrained potential motilin receptor agonists (“motilides”). A motilide pharmacophore model was generated from the potent 6,9-enol ether erythromycin and known derivatives from the literature. The pharmacophore for each molecular conformation was a point in a distance-volume space based on presentation of the putative binding moieties. Two methods, one fragment based method and the other reaction based, were explored for constructing the polyketide virtual library. First, a virtual library was assembled from monomeric fragments using the CHORTLES language. Second, the virtual library was assembled by the in silico application of all possible polyketide synthase enzyme reactions to generate the product library. Each library was converted to low-energy 3D conformations by distance geometry and standard minimization methods. The distance-volume metric was calculated for low-energy conformations of the members of the virtual polyketide library and screened against the enol ether pharmacophore. The goal was to identify novel macrocycles that satisfy the pharmacophore. We identified three conformationally constrained, novel polyketide series that have low-energy conformations satisfying the distance-volume constraints of the motilide pharmacophore.