Searching the conformational complexity and binding properties of HDAC6 through docking and molecular dynamic simulations

Abstract

Histone deacetylases (HDACs) are a family of proteins involved in the deacetylation of histones and other non-histones substrates. HDAC6 belongs to class II and shares similar biological functions with others of its class. Nevertheless, its three-dimensional structure that involves the catalytic site remains unknown for exploring the ligand recognition properties. Therefore, in this contribution, homology modeling, 100-ns-long Molecular Dynamics (MD) simulation and docking calculations were combined to explore the conformational complexity and binding properties of the catalytic domain 2 from HDAC6 (DD2-HDAC6), for which activity and affinity toward five different ligands have been reported. Clustering analysis allowed identifying the most populated conformers present during the MD simulation, which were used as starting models to perform docking calculations with five DD2-HDAC6 inhibitors: Cay10603 (CAY), Rocilinostat (RCT), Tubastatin A (TBA), Tubacin (TBC), and Nexturastat (NXT), and then were also submitted to 100-ns-long MD simulations. Docking calculations revealed that the five inhibitors bind at the DD2-HDAC6 binding site with the lowest binding free energy, the same binding mode is maintained along the 100-ns-long MD simulations. Overall, our results provide structural information about the molecular flexibility of apo and holo DD2-HDAC6 states as well as insight of the map of interactions between DD2-HDAC6 and five well-known DD2-HDAC6 inhibitors allowing structural details to guide the drug design. Finally, we highlight the importance of combining different theoretical approaches to provide suitable structural models for structure-based drug design.

Structural insights into spike protein and its natural variants of SARS-CoV-2 found on Mexican population.

“…PCA analysis is a statistical technique that allows to obtain the large scale collective motions of the atoms on the simulations, which are frequently correlated to the biological function and biophysical properties 24 . The performed method is described in detail elsewhere 25 . Structural analysis of the systems and gures were performed using PyMOL v0.99 18 .…”

Dihydropyrazole-Carbohydrazide Derivatives with Dual Activity as Antioxidant and Anti-Proliferative Drugs on Breast Cancer Targeting the HDAC6

“…All ligands interact with S568, F620, F680, H651, F679, and L749 amino acid residues (AAR) of DD2-HDAC6-the same as tubacin, TSA, and SAHA, the compounds used as reference-as well as with H611 (67% of incidence), G619 (72%), D567, T678, and Y782 (33% each), Table S4, through hydrogen bonding, electrostatic, π−π type, and mostly hydrophobic interactions, Figure 4. It is worth mentioning that these interactions are common with other recently reported HDAC6 inhibitors [62][63][64]. As can be seen, compounds 2a-i are locking the entrance to the catalytic tunnel by the 4,5-dihydro-pyrazole moiety, effectively guarding the active site of HDAC6, Figure 4.…”

Drug repositioning to target NSP15 protein on SARS‐CoV‐2 as possible COVID‐19 treatment

“…The PCA analysis is a statistical technique that allows to extract the large‐scale collective motions of the atoms from the simulations, that are often correlated to its biological function and biophysical properties 21 . The performed method is described in detail elsewhere 22 . Citrate molecule was included in the MD simulation studied; due to the fact, it was reported to be bound to the Nsp15 catalytic site of SARS‐CoV‐2 6 …”