Abstract
Confined hydration and conformational flexibility are some of the challenges encountered for the rational design of selective antagonists of G-protein coupled receptors. We present a set of C3-substituted (-)-stepholidine derivatives as potent binders of the dopamine D3 receptor. The compounds are characterized biochemically, as well as by computer modeling using a novel molecular dynamics-based alchemical binding free energy approach which incorporates the effect of the displacement of enclosed water molecules from the binding site. The free energy of displacement of specific hydration sites is obtained using the Hydration Site Analysis method with explicit solvation. This work underscores the critical role of confined hydration and conformational reorganization in the molecular recognition mechanism of dopamine receptors and illustrates the potential of binding free energy models to represent these key phenomena.
Highlights
One critical aspect of molecular recognition is the change in the hydration structure and hydration energetics induced by ligand binding. [1,2,3,4,5] Water molecules trapped, for example, in hydrophobic pockets within the binding site can be energetically disfavored as well as entropically frustrated relative to bulk water
To access the time scales required to sample the changes in hydration states and capturing the effects of water expulsion from protein binding sites induced by ligand binding. [14, 17,18,19] We have shown that the influence of confined hydration can be represented by a customized AGBNP2 [20] implicit solvent model trained on Hydration Site Analysis (HSA) [6, 8] data obtained with explicit solvation
We focus on the interaction of the D3 receptor with a series of derivatives of (-)-stepholidine (Table 1), a natural product displaying dual D1 and D2 activity and observed to have antipsychotic activities. [31, 38,39,40] Motivated by the previous work on the synthesis and activity of the (-)-stepholidine C9 derivatives [23] aimed at achieving a dual D1/D3 activity, we continued our Structure-Activity Relationship (SAR) studies using the tertrahydroprotoberberine (THPBs) scaffold to synthesize a new set of compounds targeting the dopamine receptors
Summary
One critical aspect of molecular recognition is the change in the hydration structure and hydration energetics induced by ligand binding. [1,2,3,4,5] Water molecules trapped, for example, in hydrophobic pockets within the binding site can be energetically disfavored as well as entropically frustrated relative to bulk water. [1,2,3,4,5] Water molecules trapped, for example, in hydrophobic pockets within the binding site can be energetically disfavored as well as entropically frustrated relative to bulk water. Displacements of these water molecules by the ligand can significantly enhance binding. Molecular simulations were conducted on the SuperMIC cluster at the Louisiana State University High Performance Computing Center and the Stampede II supercomputer cluster at the Texas Advanced Computing Center supported by NSF XSEDE award TG-MCB150001 to E.G. Ki determinations and receptor binding profiles were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, Contract # HHSN-271-2008-00025-C (NIMH PDSP)
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