PGVL Hub: An Integrated Desktop Tool for Medicinal Chemists to Streamline Design and Synthesis of Chemical Libraries and Singleton Compounds

Abstract

PGVL Hub is an integrated molecular design desktop tool that has been developed and globally deployed throughout Pfizer discovery research units to streamline the design and synthesis of combinatorial libraries and singleton compounds. This tool supports various workflows for design of singletons, combinatorial libraries, and Markush exemplification. It also leverages the proprietary PGVL virtual space (which contains 10(14) molecules spanned by experimentally derived synthesis protocols and suitable reactants) for lead idea generation, lead hopping, and library design. There had been an intense focus on ease of use, good performance and robustness, and synergy with existing desktop tools such as ISIS/Draw and SpotFire. In this chapter we describe the three-tier enterprise software architecture, key data structures that enable a wide variety of design scenarios and workflows, major technical challenges encountered and solved, and lessons learned during its development and deployment throughout its production cycles. In addition, PGVL Hub represents an extendable and enabling platform to support future innovations in library and singleton compound design while being a proven channel to deliver those innovations to medicinal chemists on a global scale.

Idea2Data: Toward a New Paradigm for Drug Discovery

“…Investments in automation are resulting in much improved data quality of HTS 2 , automated synthesis systems such as the ASL and the Abbvie platform, and lab-on-chip platforms for chemical synthesis and purification . These technologies, combined with advancements in synthetic knowledge, are providing practical access to sections of the chemical space much larger and more diverse than ever before. , Custom cheminformatics systems designed to manage and search chemical spaces of such dimensions enable in silico screening for the rapid identification of promising structures. , Overall, the technologies introduced seem to have reached a level of maturity to become indispensable tools in the search for new drugs. Alas, the drug discovery process has largely remained the same, centered on a sequential paradigm that progresses chemical structures from conception to assessment in steady, slow steps, and as a probable consequence, the average number of NMEs per year has not seen an analogous increase, an indication that may simply reflect the innovative capacity of the current R&D model. , …”

Does ‘Big Data’ Exist in Medicinal Chemistry, and If So, How can It Be Harnessed?

“…Researchers from Pfizer reported on the Pfizer Global Virtual Library (PGVL) of synthetically feasible compounds, which makes use of over 1200 combinatorial reactions and can theoretically enumerate 10 14 −10 18 virtual compounds [37]. A custom desktop software package, PGVL-Hub, has been developed to enable the similarity search on interested queries and design-focused libraries [38]. The impact of PGVL-Hub has been applied [39] in the discovery of novel Chk1 inhibitors, where two lead compounds were obtained through two rounds of focused library design using PGVL-Hub based on one initial HTS hit.…”

Toward a New Generation of PDE5 Inhibitors through Advances in Medicinal Chemistry

“…Unlike the lead matter triaged from the HTS, compounds designed and synthesized in a prospective manner during this library work were subjected to constraints on their physicochemistry and attractiveness. Features likely to secure a desirable PK profile were also incorporated by design through selective monomer usage and computational library design software [32]. One of the core variants identified had echoes of the pyrazolopyrimidinone found in sildenafil.…”