In Silico Positional Analogue Scanning with Amber GPU-TI

Positional analogue scanning (PAS) is an accepted strategy for multiparameter lead optimization (MPO) in drug discovery. Small structural changes as introduced by PAS can lead to 10-fold changes in binding potency in ∼10-20% of cases, a significant parameter shift irrespective of other MPO objectives. Sometimes performing a complete PAS is challenging due to resource and time constraints, building block availability, or difficulty in synthesis. Calculating relative binding free energies (RBFEs) for all positions can contribute to prioritizing the most promising analogues for synthesis. We tested a well-established RBFE calculation method, Amber GPU-TI, for 20 positional analogue scans in 14 test systems (cyclin-dependent kinase 8 (CDK8), hepatitis C virus nonstructural protein 5B (HCV NS5B), tankyrase, RAC-α serine/threonine-protein kinase (Akt), phosphodiesterase 1B (PDE1B), orexin/hypocretin receptor type 1 (OX1R), orexin/hypocretin receptor type 2 (OX2R), histone acetyltransferase K (lysine) acetyltransferase 6A (KAT6A), peroxisome proliferator-activated receptor γ (PPARγ), extracellular signal-regulated kinases (ERK1/2), coactivator-associated arginine methyltransferase 1 (PRMT4), α_vβ₆, bromodomain 1 (BD1), human immunodeficiency virus-1 (HIV-1) entry) involving nitrogen, methyl, halogen, methoxy, and hydroxyl scans with at least four analogues per set. Among the 66 analogue positions explored, we found that in 18 cases Amber GPU-TI calculations predicted a more than 10-fold change in potency. In all of these cases, the experimentally observed direction of potency changes agreed with the predictions. In 16 cases, more than 10-fold changes in experimental potency were observed. Again, in all of these cases, Amber GPU-TI predicted the direction of the potency changes correctly. In none of these cases would a decision made for or against synthesis based on a 10-fold change in potency have resulted in missing an important analogue. Therefore, in silico RBFE calculations using Amber GPU-TI can meaningfully contribute to the prioritization of positional analogues before synthesis.