Abstract
We report on the development of a cheminformatics enumeration technology and the analysis of a resulting large dataset of virtual macrolide scaffolds. Although macrolides have been shown to have valuable biological properties, there is no ready-to-screen virtual library of diverse macrolides in the public domain. Conducting molecular modeling (especially virtual screening) of these complex molecules is highly relevant as the organic synthesis of these compounds, when feasible, typically requires many synthetic steps, and thus dramatically slows the discovery of new bioactive macrolides. Herein, we introduce a cheminformatics approach and associated software that allows for designing and generating libraries of virtual macrocycle/macrolide scaffolds with user-defined constitutional and structural constraints (e.g., types and numbers of structural motifs to be included in the macrocycle, ring size, maximum number of compounds generated). To study the chemical diversity of such generated molecules, we enumerated V1M (Virtual 1 million Macrolide scaffolds) library, each containing twelve common structural motifs. For each macrolide scaffold, we calculated several key properties, such as molecular weight, hydrogen bond donors/acceptors, topological polar surface area. In this study, we discuss (1) the initial concept and current features of our PKS (polyketides) Enumerator software, (2) the chemical diversity and distribution of structural motifs in V1M library, and (3) the unique opportunities for future virtual screening of such enumerated ensembles of macrolides. Importantly, V1M is provided in the Supplementary Material of this paper allowing other researchers to conduct any type of molecular modeling and virtual screening studies. Therefore, this technology for enumerating extremely large libraries of macrolide scaffolds could hold a unique potential in the field of computational chemistry and drug discovery for rational designing of new antibiotics and anti-cancer agents.
Highlights
Macrocycles are ring structures composed of at least twelve atoms in the central cyclic framework [1,2,3]
Of particular interest are macrolides, i.e., glycosylated macrocyclic lactones belonging to the class of polyketides (PKS) that represent an important family of bioactive molecules [4,5,6], Macrolides have critical therapeuticallyrelevant applications [7], such as antibiotics (e.g. Erythromycin, Telithromycin, Clarithromycin, Azithromycin [8]) and anticancer agents
We had the Structural diversity We reported on the distribution, composition of Common Structural Motif (CSM) types, their occurrence(s) per macrolide scaffold, along with the distribution of heteroatoms and heavyatoms observed in virtual 1 million macrolide scaffolds (V1M)
Summary
Macrocycles are ring structures composed of at least twelve atoms in the central cyclic framework [1,2,3]. Of particular interest are macrolides, i.e., glycosylated macrocyclic lactones belonging to the class of polyketides (PKS) that represent an important family of bioactive molecules [4,5,6], Macrolides have critical therapeuticallyrelevant applications [7], such as antibiotics (e.g. Erythromycin, Telithromycin, Clarithromycin, Azithromycin [8]) and anticancer agents (e.g. Dactinomycin, Cyclosporine, Temsirolimus, Sirolimus [8]) (see Fig. 1). They have been broadly investigated in modern drug discovery programs as antifungal, antiparasitic, antiproliferative, antituberculosis, and antiviral agents [8].
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