Evaluating New Chemistry to Drive Molecular Discovery: Fit for Purpose?

Abstract

As our understanding of the impact of specific molecular properties on applications in discovery-based disciplines improves, the extent to which published synthetic methods meet (or do not meet) desirable criteria is ever clearer. Herein, we show how the application of simple (and in many cases freely available) computational tools can be used to develop a semiquantitative understanding of the potential of new methods to support molecular discovery. This analysis can, among other things, inform the design of improved substrate scoping studies; direct the prioritization of specific exemplar structures for synthesis; and substantiate claims of potential future applications for new methods.

Keywords: computational tools; lead-oriented synthesis; molecular discovery; molecular properties; synthetic chemistry.

Figure 1

Reported variable groups in synthetic methodology papers in the first issues in 2016 of Angew. Chem. Int. Ed. and J. Am. Chem. Soc. (see the Supporting Information). A) Variation in terms of aryl and hetaryl substitution. B) The proportion of functionalizable (het)aryl versus unfunctionalizable (het)aryl groups incorporated. C) Variation of phenyl substitution. Charts are scaled according to the number of examples in the data set [504 examples for (A) and (B), 321 examples for (C)].

Figure 2

Willis’ approach to the synthesis of sulfonamides from organometallic reagents, DABSO, and amines.21 A) Synthesis of an exemplar sulfonamide. B) Molecular properties of the products of an array of 7 organometallic reagents and 10 amines described in the paper. The property space corresponding to Lipinski's guidelines for orally bioavailable drugs (dashed grey line), and Clarke's parameters for insecticides (black line), fungicides (solid grey line), and herbicides (dashed black line) are indicated. DABSO is the bis‐SO₂ adduct of 1,4‐diazabicyclo[2.2.2]octane (DABCO).

Figure 3

Synthesis of 2,5‐disubstituted pyrrolidines using Pd‐catalyzed aminoarylation reactions. A) Synthesis of pyrrolidine 1 a, as reported by Wolfe.22a B) Pyrrolidines that might also be accessible using the method. C) Mean molecular properties of virtual libraries derived from the scaffolds 1. In each case, the Boc group was removed and the scaffold was decorated once using a range of standard capping groups. Lipinski's guidelines for orally bioavailable drugs are indicated by the solid black line. Novel scaffolds (compared to a random 2 % selection of the ZINC database) are shown in black, whilst known substructures are shown in grey. Standard deviations are indicated.

Figure 4

Bode's approach to nitrogen‐containing heterocycles using SnAP reagents.23 A) Exemplar reaction of benzaldehyde with a SnAP reagent. B) Additional scaffolds that have been, or might be, prepared from benzaldehyde using the approach. C) Mean molecular properties of virtual libraries derived from scaffolds 3 after one decoration reaction. Novel scaffolds are shown in black, whilst those that are found as substructures in a random 2 % sample from the ZINC database are shown in grey. Standard deviations are shown. Lead‐like molecular property space5 is indicated by the black box.

Figure 5

Assessment of the relevance of scaffolds to CNS drug discovery. A) The scaffolds considered in this study.26 B) Mean molecular properties of virtual libraries derived from the scaffolds 4–11 after one decoration. Standard deviations are shown. Molecular property space is shaded according to Pfizer's guidelines for relevance to CNS drug discovery (pale pink: optimal, dark pink: transitional area, red: undesirable).19

Figure 6

Evaluation of the shape diversity of virtual libraries based on spirocyclic scaffolds reported by Carreira and Rogers‐Evans.27 A) The scaffolds evaluated in this study. B) Mean principal moments of inertia of virtual libraries generated by decoration of the scaffolds once or twice using the standard set of capping groups. See the Supporting Information for further details.

Figure 7

Bull's approach to substituted oxetanes.31 A) Synthesis of an exemplar oxetane (R=Bn, which was virtually removed before the computational study). B) Other scaffolds that were combined with 28 small amines to yield a virtual library of amides (see the Supporting Information). C) PMI plot of the 61 fragment‐like compounds found in the virtual library (black), 257 fragments randomly selected from the e‐molecules database (light gray) and 261 fragments randomly selected from the GDB‐17 database (dark gray). A plane‐of‐best‐fit analysis (Ref. 30) is also provided in the Supporting Information.