Exploration of Ultralarge Compound Collections for Drug Discovery

Abstract

Designing new medicines more cheaply and quickly is tightly linked to the quest of exploring chemical space more widely and efficiently. Chemical space is monumentally large, but recent advances in computer software and hardware have enabled researchers to navigate virtual chemical spaces containing billions of chemical structures. This review specifically concerns collections of many millions or even billions of enumerated chemical structures as well as even larger chemical spaces that are not fully enumerated. We present examples of chemical libraries and spaces and the means used to construct them, and we discuss new technologies for searching huge libraries and for searching combinatorially in chemical space. We also cover space navigation techniques and consider new approaches to de novo drug design and the impact of the "autonomous laboratory" on synthesis of designed compounds. Finally, we summarize some other challenges and opportunities for the future.

Modeling the expansion of virtual screening libraries

“…An opportunity to do so has come with the advent of ultra-large make-on-demand or "tangible" libraries 20 . These virtual libraries are composed of molecules that have not been previously made, but can readily be synthesized.…”

ViSAS for Entering Chemical Space: Virtual Screening of Analog Series and Related Advances

“…[15] Other databases that are having a major current trend in drug discovery are virtual compound libraries and de novo designed libraries. [29] Also, it is ongoing an effort to build and curate a compound database with metal-containing molecules in preclinical and clinical development, and approved for therapeutic use. [30] Natural products have been sources of bioactive compounds that later have been used in the clinic or that have been used as starting points of drug candidates.…”

“…However, the rapid and continued increase of large-and ultra-large libraries has renewed the interest of the scientific community to generate/implement methods to handle and use for practical applications the largeand ultra-large chemical space associated with the newly generated compound libraries. [29] Hence, the chemical space concept continues to be of significant interest to study the very large chemical libraries. There are several reviews addressing the concept of chemical space, covering different aspects such as enumeration of chemical compounds using de novo design, calculation of molecular descriptors, progress on visualization methods with emphasis on publicly available tools, web servers to explore the chemical space of chemical libraries, applications to study structure-property relationships.…”

Chemical Multiverse: An Expanded View of Chemical Space

“…The For several decades, the chemical space concept has been of interest in several areas of chemistry, emphasizing drug discovery. With the rapid advances in machine learning and de novo design and the number of chemical compounds that exist or could be made, the community has a significant interest toward enumerating large-and ultra-large chemical libraries containing billions of chemical structures [8]. Hence, there is an increased interest in analyzing, exploring, and generating visual representations of the extensive chemical libraries under the chemical space concept.…”