Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0699790 (
colon cancer
)
28,837
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Mono-polar spindle 1 (Mps1/TTK) represents a protein kinase reported to be vital for cell division processes and is generally regarded as an attractive target for the treatment of hepatocellular carcinoma, breast carcinoma, and
colon cancer
. However, the C604Y mutation has been linked to acquired resistance. Recently, three potential small-molecule inhibitors of Mps1 (i.e., reversine,
NMS
-P715, and its derivative Cpd-5) were reported for the C604Y mutation that exhibit significant resistance to
NMS
-P715 and Cpd-5, but retain affinity for reversine. In this study, classical molecular dynamic (MD) simulations, accelerated MD (aMD) simulations, and umbrella sampling (US) simulations were performed to illustrate the resistance mechanisms of inhibitors to Mps1. The classical MD simulations combined with free energy calculations revealed that reversine features similar binding affinity characteristics to both Mps1
WT
and Mps1
C604Y
, but both
NMS
-P715 and Cpd-5 feature much higher binding affinities to Mps1
WT
than to Mps1
C604Y
. The major variations were shown to be controlled by electrostatic energy and the conformational change of A-loop-induced entropy increased. The large conformational changes of Mps1
C604Y
bound to
NMS
-P715 and Cpd-5 were also observed in aMD simulations. The US simulation results further suggest that reversine and Cpd-5 both exhibit similar dissociation processes from both Mps1
WT
and Mps1
C604Y
, but Cpd-5 and
NMS
-P715 were found to dissociate more easily from Mps1
C604Y
than from Mps1
WT
, thus a reduced residence time was responsible for the inhibitors resistance to the C604Y mutation. The physical principles provided by the present study may provide important clues for the discovery and rational design of novel inhibitors to combat the C604Y mutation of Mps1.
...
PMID:Insights into Resistance Mechanisms of Inhibitors to Mps1 C604Y Mutation via a Comprehensive Molecular Modeling Study. 2992 69
