Emergent synthetic methods for the modular advancement of sp³-rich fragments

Abstract

Fragment-based drug discovery is an important and increasingly reliable technology for the delivery of clinical candidates. Notably, however, sp3-rich fragments are a largely untapped resource in molecular discovery, in part...

Unsupervised Machine Learning Approach for Identifying Biomechanical Influences on Protein-Ligand Binding Affinity

“…Therefore, multicollinearity analysis will validate the presence of the larger substructure (containing CCCH and CCCCCH fragments) suggested in this study's results [47]. Should it exist, in-vitro experimentation can be performed to determine how the substructure affects ML performance in predicting binding affinity, revealing important information on the usefulness of such substructures in VS [49]. In addition, the protein-ligand models used in this study came from a single dataset, which introduces dataset bias and may affect the results of feature analysis.…”

Remote ortho-C–H functionalization via medium-sized cyclopalladation

“…34 Pd(OAc) 2 (10 mol%) and Ag 2 CO 3 in super-stoichiometric amount was found to be the best catalyst and oxidant combination, along with (n-BuO) 2 PO 2 H as additive in DCE at 120 1C for 24 h. This method was successfully applied to a wide range of olefins, such as terminal alkyl olefins, allyl alcohol derivatives, acrylaldehyde, allyl acetate, acrylates, and acrylonitrile (1-7). The scope of the reaction includes phenylpropylamine derivatives bearing different substitution patterns in the aromatic ring (8)(9)(10)(11)(12)(13)(14)(15)(16). In all cases studied, the methylene g-C-H bonds, whose activation would involve five-membered cyclopalladation, remained unaltered.…”

“…[1][2][3][4][5][6][7][8][9][10] Despite the extensive progress made, achieving high site selectivity control is still a prominent goal in the field. [11][12][13][14][15][16] A successful approach towards this goal is the use of directing groups (DGs) to assist the C-H metalation step. A DG is a Lewis basic entity that acts as a ligand for the metal and brings the active catalytic species into close proximity to the desired C-H bond.…”

C–H functionalisation tolerant to polar groups could transform fragment-based drug discovery (FBDD)

“…When these facts are considered it could be reasoned that the disproportionate occurrence of bonds formed with sp 3 -character 47 in relation to sp 2 -character could be attributed to synthetic challenges that their inclusion presents. A recent Perspective by Caplin and Foley 48 further emphasises the challenges associated with sp 3 -rich fragments as well as highlighting recent advances in C(sp 3 )–H functionalisation which are beginning to have an impact in this area.…”