Origin of the kinetic HDAC2‐selectivity of an HDAC inhibitor

Abstract

A newly synthesized small molecule, KTT‐1, exhibits kinetically selective inhibition of histone deacetylase 2, HDAC2, over its homologous enzyme, HDAC1. KTT‐1 is hard to be released from the HDAC2/KTT‐1 complex, compared to the HDAC1/KTT‐1 complex and the residence time of KTT‐1 in HDAC2 is longer than that in HDAC1. To explore the physical origin of this kinetic selectivity, we performed replica‐exchange umbrella sampling molecular dynamics simulations for formation of both complexes. The calculated potentials of mean force suggest that KTT‐1 is stably bound to HDAC2 and that it is easily disassociated from HDAC1. In the direct vicinity of the KTT‐1 binding site in both enzymes, there exists a conserved loop consisting of four consecutive glycine residues (Gly304‐307 for HDAC2; Gly299‐302 for HDA1). The difference between the two enzymes comes from a single un‐conserved residue behind this loop, namely, Ala268 in HDAC2 and Ser263 in HDAC1. The Ala268 contributes to the tight binding of KTT‐1 to HDAC2 by the linear orientation of Ala268, Gly306, and one carbon atom in KTT‐1. On the other hand, Ser263 cannot stabilize the binding of KTT‐1 to HDAC1, because it is relatively further away from the glycine loop and because the directions of the two forces are not in line.

Evolution of Slow-Binding Inhibitors Targeting Histone Deacetylase Isoforms

“…The rational design of slow-binding inhibitors requires a synergistic approach involving both experimental and computational methods. 10 This synergy aims to create compounds that establish enduring and stable complexes with the target enzyme, resulting in a prolonged inhibition. This process would begin with the execution of a thorough investigation of the enzyme's structure.…”

“…These dynamic properties are crucial for comprehending the time-dependent interactions between 45 and HDAC2, which ultimately contribute to the observed kinetic selectivity. To comprehensively investigate the physical basis of this kinetic selectivity, the authors utilized advanced molecular dynamics simulations via replica-exchange umbrella sampling . Using this method, the authors meticulously investigated the formation of both 45 :HDAC2 and 45 :HDAC1 complexes and found that although 45 formed a highly stable interaction with HDAC2, it readily dissociated from HDAC1.…”

“…The green, orange, and purple spheres are the C β atom of Ser263/Ala268, the C α atom of Gly301/306, and the C3 atom of inhibitor 45 , respectively. Reproduced with permission from ref . Copyright 2023 Wiley-VCH.…”

“…2−5 Additionally, t R impacts the selectivity of a drug's interaction with pharmacological proteins. 9,10 If a drug has a long residence time on its target, the drug's pharmacokinetic lifetime is exceeded during the systematic circulation, which can lead to a high selectivity for the intended target. 2−5 Recent studies have suggested that prolonged in vivo drug−target binding can protect drugs against being metabolized by minimizing both the drugs' binding to other proteins, including metabolic enzymes, and excretion.…”

“…However, this static definition of selectivity does not include the residence time on the target compared with those on off-target biomolecules. Therefore, the drug selectivity should also be considered as a time-dependent parameter. − Additionally, t R impacts the selectivity of a drug’s interaction with pharmacological proteins. , If a drug has a long residence time on its target, the drug’s pharmacokinetic lifetime is exceeded during the systematic circulation, which can lead to a high selectivity for the intended target. − Recent studies have suggested that prolonged in vivo drug–target binding can protect drugs against being metabolized by minimizing both the drugs’ binding to other proteins, including metabolic enzymes, and excretion. This could explain why certain compounds may exhibit an unexpectedly long elimination half-life .…”