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A computational insight into the effect of deuteration on the H2 receptor histamine binding profile

In the past few years, deuteration has become one of the most promising tools in medicinal chemistry to overcome problems in terms of metabolism- mediated toxicity, low bioactivation, and drug interactions. Furthermore, precise deuteration goes beyond the pure and simple amelioration of the pharmacokinetic properties, providing an opportunity to decrease the degree of racemisation, reduce the dose of coadministered boosters, and contribute to the investigation of mechanisms of action for various endo- and xenobiotics [1]. In this work, we used a range of computational techniques to reveal an increased histamine affinity for its H2 receptor upon nonselective deuteration, which was interpreted through altered hydrogen bonds within the receptor and the aqueous solution preceding the binding [2]. Molecular docking procedure identified the area between third and fifth transmembrane α-helices as the likely binding site. The subsequent molecular dynamics simulation recognized Asp98 as the most dominant residue, whose persistent hydrogen bond with the histamine −NH3+ group accounts for the 40% of the total binding energy, and is further stabilised through interaction with Tyr250 (Figure 1). Lastly, quantum-chemical calculations supported the deuteration-induced affinity increase by calculating the difference in the binding free energy of −0.85 kcal mol−1, which is in excellent agreement with an experimental value of −0.75 kcal mol−1. All these calculations confirm the initial hypothesis that hydrogen bonds are crucial in the H2 receptor activation and underline precise deuteration as a useful tool to improve drug efficiency. [1] T. Pirali, M. Serafini, S. Cargnin, A. A. Genazzani, J. Med. Chem. 62 (2019) 5276−5297. [2] L. Hok, J. Mavri, R. Vianello, Molecules 25 (2020) 6017.

deuteration ; heavy drugs ; histamine receptor ; hydrogen bonding ; receptor activation

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