PMID- 36053294
OWN - NLM
STAT- MEDLINE
DCOM- 20220928
LR  - 20221018
IS  - 1549-960X (Electronic)
IS  - 1549-9596 (Linking)
VI  - 62
IP  - 18
DP  - 2022 Sep 26
TI  - In Silico Positional Analogue Scanning with Amber GPU-TI.
PG  - 4448-4459
LID - 10.1021/acs.jcim.2c00860 [doi]
AB  - 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  approximately 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-alpha 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 gamma 
      (PPARgamma), extracellular signal-regulated kinases (ERK1/2), coactivator-associated 
      arginine methyltransferase 1 (PRMT4), alpha(v)beta(6), 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.
FAU - Hu, Yuan
AU  - Hu Y
AUID- ORCID: 0000-0002-1014-6594
AD  - Alkermes, Inc., 852 Winter Street, Waltham, Massachusetts 02451-1420, United 
      States.
FAU - Muegge, Ingo
AU  - Muegge I
AUID- ORCID: 0000-0003-3294-1852
AD  - Alkermes, Inc., 852 Winter Street, Waltham, Massachusetts 02451-1420, United 
      States.
LA  - eng
PT  - Journal Article
DEP - 20220902
PL  - United States
TA  - J Chem Inf Model
JT  - Journal of chemical information and modeling
JID - 101230060
RN  - 0 (Amber)
RN  - 0 (Halogens)
RN  - 0 (Orexin Receptors)
RN  - 0 (Orexins)
RN  - 0 (PPAR gamma)
RN  - 2ZD004190S (Threonine)
RN  - 452VLY9402 (Serine)
RN  - EC 2.3.1.48 (Histone Acetyltransferases)
RN  - EC 2.4.2.30 (Tankyrases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinase 8)
RN  - EC 3.1.4.- (Phosphoric Diester Hydrolases)
RN  - K3Z4F929H6 (Lysine)
RN  - N762921K75 (Nitrogen)
SB  - IM
MH  - Amber
MH  - Cyclin-Dependent Kinase 8
MH  - Halogens
MH  - Histone Acetyltransferases
MH  - Humans
MH  - Lysine
MH  - Nitrogen
MH  - Orexin Receptors
MH  - Orexins
MH  - *PPAR gamma
MH  - Phosphoric Diester Hydrolases
MH  - Proto-Oncogene Proteins c-akt
MH  - Serine
MH  - *Tankyrases
MH  - Threonine
EDAT- 2022/09/03 06:00
MHDA- 2022/09/28 06:00
CRDT- 2022/09/02 11:13
PHST- 2022/09/03 06:00 [pubmed]
PHST- 2022/09/28 06:00 [medline]
PHST- 2022/09/02 11:13 [entrez]
AID - 10.1021/acs.jcim.2c00860 [doi]
PST - ppublish
SO  - J Chem Inf Model. 2022 Sep 26;62(18):4448-4459. doi: 10.1021/acs.jcim.2c00860. 
      Epub 2022 Sep 2.