TY - JOUR
T1 - Structural and energetic basis for the inhibitory selectivity of both catalytic domains of dimeric HDAC6
AU - Sixto-López, Yudibeth
AU - Bello, Martiniano
AU - Correa-Basurto, José
N1 - Publisher Copyright:
© 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2019/12/12
Y1 - 2019/12/12
N2 - HDAC6 is a protein involved in cancer, neurodegenerative disease and inflammatory disorders. To date, the full three-dimensional (3D) structure of human HDAC6 has not been elucidated; however, there are some experimental 3D structural homologs to HDAC6 that can be used as templates. In this work, we utilized molecular modeling procedures to model both of the catalytic domains of HDAC6 connected by the linker region where DMB region is placed. Once the 3D structure of human HDAC6 was obtained, it was structurally evaluated and submitted to docking and molecular dynamic (MD) simulations along with Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) method to explore the stability and the binding free energy properties of the HDAC6–ligand complexes. In addition, its structural and energetic behavior was explored with each one of the catalytic domains in the molecular recognition of six selective HDAC6 inhibitors, HPOB, CAY10603, Nexturastat, Rocilinostat, Tubacin and Tubastatin A for DD2, and with the so-called 9-peptide which is DD1–HDAC6 selective substrate. The use of the whole system (DD1–DMB–DD2) showed a tendency toward the ligand affinity of DD2, CAY10603> Tubacin > Rocilinostat > Nexturastat > HPOB > Tubastatin > 9-peptide, which is in line with experimental reports. However, 9-peptide showed a higher affinity for DD1, which agrees with experimental reports elsewhere. Principal component analysis provided important information about the structural changes linked to the molecular recognition process, whereas per-residue decomposition analysis revealed the energetic contribution of the key residues in the molecular binding and structural characteristics that could assist in drug design.
AB - HDAC6 is a protein involved in cancer, neurodegenerative disease and inflammatory disorders. To date, the full three-dimensional (3D) structure of human HDAC6 has not been elucidated; however, there are some experimental 3D structural homologs to HDAC6 that can be used as templates. In this work, we utilized molecular modeling procedures to model both of the catalytic domains of HDAC6 connected by the linker region where DMB region is placed. Once the 3D structure of human HDAC6 was obtained, it was structurally evaluated and submitted to docking and molecular dynamic (MD) simulations along with Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) method to explore the stability and the binding free energy properties of the HDAC6–ligand complexes. In addition, its structural and energetic behavior was explored with each one of the catalytic domains in the molecular recognition of six selective HDAC6 inhibitors, HPOB, CAY10603, Nexturastat, Rocilinostat, Tubacin and Tubastatin A for DD2, and with the so-called 9-peptide which is DD1–HDAC6 selective substrate. The use of the whole system (DD1–DMB–DD2) showed a tendency toward the ligand affinity of DD2, CAY10603> Tubacin > Rocilinostat > Nexturastat > HPOB > Tubastatin > 9-peptide, which is in line with experimental reports. However, 9-peptide showed a higher affinity for DD1, which agrees with experimental reports elsewhere. Principal component analysis provided important information about the structural changes linked to the molecular recognition process, whereas per-residue decomposition analysis revealed the energetic contribution of the key residues in the molecular binding and structural characteristics that could assist in drug design.
KW - CAY10603
KW - DD1
KW - DD2
KW - HDAC6 inhibitors
KW - HPOB
KW - Histone deacetylases 6
KW - MM/GBSA
KW - Nexturastat
KW - Rocilinostat
KW - Tubacin
KW - Tubastatin
KW - molecular dynamic simulation
UR - http://www.scopus.com/inward/record.url?scp=85061441859&partnerID=8YFLogxK
U2 - 10.1080/07391102.2018.1557560
DO - 10.1080/07391102.2018.1557560
M3 - Artículo
C2 - 30558483
AN - SCOPUS:85061441859
SN - 0739-1102
VL - 37
SP - 4701
EP - 4720
JO - Journal of Biomolecular Structure and Dynamics
JF - Journal of Biomolecular Structure and Dynamics
IS - 18
ER -