TY - JOUR
T1 - Exploring the inhibitory activity of valproic acid against the HDAC family using an MMGBSA approach
AU - Sixto-López, Yudibeth
AU - Bello, Martiniano
AU - Correa-Basurto, José
N1 - Publisher Copyright:
© 2020, Springer Nature Switzerland AG.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - Valproic acid (VPA) is a compound currently used in clinical practice for the treatment of epilepsy as well as bipolar and mood disorders. VPA targets histone deacetylases (HDACs), which participate in the removal of acetyl groups from lysine in several proteins, regulating a wide variety of functions within the organism. An imbalance or malfunction of these enzymes is associated with the development and progression of several diseases, such as cancer and neurodegenerative diseases. HDACs are divided into four classes, but VPA only targets Class I (HDAC1–3 and 8) and Class IIa (HDAC4–5, 7 and 9) HDACs; however, structural and energetic information regarding the manner by which VPA inhibits these HDACs is lacking. Here, the structural and energetic features that determine this recognition were studied using molecular docking and molecular dynamics (MD) simulation. It was found that VPA reaches the catalytic site in HDAC1–3 and 7, whereas in HDAC6, VPA only reaches the catalytic tunnel. In HDAC4, VPA was bound adjacent to L1 and L2, a zone that participates in corepressor binding, and in HDAC8, VPA was bound to the hydrophobic active site channel (HASC), in line with previous reports.
AB - Valproic acid (VPA) is a compound currently used in clinical practice for the treatment of epilepsy as well as bipolar and mood disorders. VPA targets histone deacetylases (HDACs), which participate in the removal of acetyl groups from lysine in several proteins, regulating a wide variety of functions within the organism. An imbalance or malfunction of these enzymes is associated with the development and progression of several diseases, such as cancer and neurodegenerative diseases. HDACs are divided into four classes, but VPA only targets Class I (HDAC1–3 and 8) and Class IIa (HDAC4–5, 7 and 9) HDACs; however, structural and energetic information regarding the manner by which VPA inhibits these HDACs is lacking. Here, the structural and energetic features that determine this recognition were studied using molecular docking and molecular dynamics (MD) simulation. It was found that VPA reaches the catalytic site in HDAC1–3 and 7, whereas in HDAC6, VPA only reaches the catalytic tunnel. In HDAC4, VPA was bound adjacent to L1 and L2, a zone that participates in corepressor binding, and in HDAC8, VPA was bound to the hydrophobic active site channel (HASC), in line with previous reports.
KW - HDAC
KW - Histone deacetylases
KW - MMGBSA
KW - Molecular dynamics simulation
KW - VPA
KW - Valproic acid
UR - http://www.scopus.com/inward/record.url?scp=85082765433&partnerID=8YFLogxK
U2 - 10.1007/s10822-020-00304-2
DO - 10.1007/s10822-020-00304-2
M3 - Artículo
C2 - 32180123
SN - 0920-654X
VL - 34
SP - 857
EP - 878
JO - Journal of Computer-Aided Molecular Design
JF - Journal of Computer-Aided Molecular Design
IS - 8
ER -