PMID- 37029757
OWN - NLM
STAT- MEDLINE
DCOM- 20231219
LR  - 20231219
IS  - 1538-0254 (Electronic)
IS  - 0739-1102 (Linking)
VI  - 41
IP  - 24
DP  - 2023
TI  - Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) inhibitors: a novel 
      approach in small molecule discovery.
PG  - 15196-15206
LID - 10.1080/07391102.2023.2193999 [doi]
AB  - The calcium/calmodulin dependent protein kinase kinase 2 (CAMKK2) plays a key 
      role in regulation of intracellular calcium levels and signaling pathways. It is 
      involved in activation of downstream signaling pathways that regulate various 
      cellular processes. Dysregulation of CAMKK2 activity has been linked to various 
      diseases including cancer, suggesting that CAMKK2 inhibitors might be beneficial 
      in oncological, metabolic and inflammatory indications. The most pressing issues 
      in small molecule discovery are synthesis feasibility, novel chemical structure 
      and desired biological characteristics. To circumvent this constraint, we 
      employed 'DrugspaceX' for rapid lead identification, followed by repositioning 
      seven FDA-approved drugs for CAMKK2 inhibition. Further, first-level 
      transformation (Set1 analogues) was performed in 'DrugspaceX', followed by 
      virtual screening. The t-SNE visualization revealed that the transformations 
      surrounding Rucaparib, Treprostinil and Canagliflozin are more promising for 
      developing CAMKK2 inhibitors. Second, using the top-ranked Set1 analogues, Set2 
      analogues were generated, and virtual screening revealed the top-ranked five 
      analogues. Among the top five Set2 analogues, DE273038_5 had the lowest docking 
      score of -11.034 kcal/mol and SA score of 2.59, retaining the essential 
      interactions with Hotspot residues LYS194 and VAL270 across 250 ns simulation 
      period. When compared to the other four compounds, the ligand effectiveness score 
      was 0.409, and the number of rotatable penalties was only three. Further, 
      DE273038_5 after two rounds of transformations was discovered to be novel and had 
      not been previously described in other databases. These data suggest that the new 
      candidate DE273038_5 is likely to have inhibitory activity at the CAMKK2 active 
      site, implying potential therapeutic use.Communicated by Ramaswamy H. Sarma.
FAU - Devasahayam Arokia Balaya, Rex
AU  - Devasahayam Arokia Balaya R
AUID- ORCID: 0000-0002-9556-3150
AD  - Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), 
      Mangalore, Karnataka, India.
FAU - Chandrasekaran, Jaikanth
AU  - Chandrasekaran J
AUID- ORCID: 0000-0002-5088-9683
AD  - Sri Ramachandra Faculty of Pharmacy, Sri Ramachandra Institute of Higher 
      education and Research (Deemed to be University), Chennai, India.
FAU - Kanekar, Saptami
AU  - Kanekar S
AUID- ORCID: 0000-0002-1508-5305
AD  - Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), 
      Mangalore, Karnataka, India.
FAU - Kumar Modi, Prashant
AU  - Kumar Modi P
AUID- ORCID: 0000-0002-4817-3379
AD  - Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, 
      Yenepoya (Deemed to be University), Mangalore, Karnataka, India.
FAU - Dagamajalu, Shobha
AU  - Dagamajalu S
AUID- ORCID: 0000-0002-0899-2839
AD  - Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, 
      Yenepoya (Deemed to be University), Mangalore, Karnataka, India.
FAU - Gopinathan, Kirthika
AU  - Gopinathan K
AUID- ORCID: 0000-0002-1670-4411
AD  - Sri Ramachandra Faculty of Pharmacy, Sri Ramachandra Institute of Higher 
      education and Research (Deemed to be University), Chennai, India.
FAU - Raju, Rajesh
AU  - Raju R
AUID- ORCID: 0000-0003-2319-121X
AD  - Centre for Integrative Omics Data Science, Yenepoya (Deemed to be University), 
      Mangalore, Karnataka, India.
FAU - Prasad, T S Keshava
AU  - Prasad TSK
AUID- ORCID: 0000-0002-6206-2384
AD  - Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, 
      Yenepoya (Deemed to be University), Mangalore, Karnataka, India.
LA  - eng
PT  - Journal Article
DEP - 20230408
PL  - England
TA  - J Biomol Struct Dyn
JT  - Journal of biomolecular structure & dynamics
JID - 8404176
RN  - SY7Q814VUP (Calcium)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Kinase)
SB  - IM
MH  - *Calcium/metabolism
MH  - *Calcium-Calmodulin-Dependent Protein Kinase Kinase/chemistry/metabolism
MH  - Catalytic Domain
MH  - Signal Transduction
OTO - NOTNLM
OT  - CAMKK2 inhibitors
OT  - MD simulation
OT  - analogues
OT  - docking
OT  - t-SNE
EDAT- 2023/04/09 06:00
MHDA- 2023/12/19 06:42
CRDT- 2023/04/08 09:32
PHST- 2023/12/19 06:42 [medline]
PHST- 2023/04/09 06:00 [pubmed]
PHST- 2023/04/08 09:32 [entrez]
AID - 10.1080/07391102.2023.2193999 [doi]
PST - ppublish
SO  - J Biomol Struct Dyn. 2023;41(24):15196-15206. doi: 10.1080/07391102.2023.2193999. 
      Epub 2023 Apr 8.