The D3 Process extended

D3 uses an approach that establishes a tight link between:

  • What molecules can be made (D3 virtual catalogs)
  • What molecules should be made (from computational analyses of these D3 virtual catalogs)
  • Synthesis of the selected molecules (via D3 procedures) [D3 Equipment]
  • Evaluation of these molecules for potential activity against neglected disease targets (centralized or D3 based screening)

 

D3 is based on a process that is unconventional. The classic computational approach would start with a single, defined, biologically determined molecular target and then design and synthesize a molecule to modulate the activity of that target (“Classic”, Scheme 1). This process is limited by the time it takes to synthesize molecules individually designed by a computational expert. This expert may not understand that making the molecule could be quite difficult. This in turn restricts their ability to quickly test hypotheses and gather molecule-based experimental data to refine their computational models.

 

Instead D3 first creates very general and powerful synthetic D3 methodologies giving access to large classes of biomimetic molecules with precedented and varied biological activity. It enumerates large D3 virtual catalogs based on these procedures. Now the expert computational chemist has a large collection of virtual molecules to search for subsets that will test their hypothesis.. Selected molecules identified by this process now have a strong probability of being reproducibly synthesized, at low cost and with simple equipment, by students anywhere in the world (“D3 Based”, Scheme 1). They can then be evaluated by centralized or distributed biological models.

Scheme 1. Classic and D3 based approaches

The beauty of D3 is that each discipline can independently develop the tools for this process at the same time all can benefit from each other’s expertise. Once the investment of time and talent has been made in creating the D3 virtual catalogs the selected target molecules can be rapidly and reproducibly synthesized, with the likelihood that follow up optimization work can also be rapidly done with molecules identified from the virtual catalogs.

D3’s primary focus is neglected disease drug discovery. It seeks to recruit and empower computational experts to help select appropriate potential drug molecules for D3 synthesis. This process is illustrated in Scheme 2. Immunologists will be amused to see that this “survival of the fittest” process - minus the computational modeling, and with the entire “virtual” library all ready existing as part of the immunoglobulin repertoire - closely resembles the body’s antibody response system to foreign invasion.

Scheme 2. Selection of molecules for D3 synthesis