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Article

Potency-Enhancing Mutations of Gating Modifier Toxins for the Voltage-Gated Sodium Channel NaV1.7 Can Be Predicted Using Accurate Free-Energy Calculations

Schrӧdinger, Inc., 120 West 45th St., New York, NY 10036, USA
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Toxins 2021, 13(3), 193; https://doi.org/10.3390/toxins13030193
Received: 1 February 2021 / Revised: 1 March 2021 / Accepted: 3 March 2021 / Published: 7 March 2021
(This article belongs to the Special Issue Advances in Structure-Based Drug Design of Venom Peptides)
Gating modifier toxins (GMTs) isolated from venomous organisms such as Protoxin-II (ProTx-II) and Huwentoxin-IV (HwTx-IV) that inhibit the voltage-gated sodium channel NaV1.7 by binding to its voltage-sensing domain II (VSDII) have been extensively investigated as non-opioid analgesics. However, reliably predicting how a mutation to a GMT will affect its potency for NaV1.7 has been challenging. Here, we hypothesize that structure-based computational methods can be used to predict such changes. We employ free-energy perturbation (FEP), a physics-based simulation method for predicting the relative binding free energy (RBFE) between molecules, and the cryo electron microscopy (cryo-EM) structures of ProTx-II and HwTx-IV bound to VSDII of NaV1.7 to re-predict the relative potencies of forty-seven point mutants of these GMTs for NaV1.7. First, FEP predicted these relative potencies with an overall root mean square error (RMSE) of 1.0 ± 0.1 kcal/mol and an R2 value of 0.66, equivalent to experimental uncertainty and an improvement over the widely used molecular-mechanics/generalized born-surface area (MM-GB/SA) RBFE method that had an RMSE of 3.9 ± 0.8 kcal/mol. Second, inclusion of an explicit membrane model was needed for the GMTs to maintain stable binding poses during the FEP simulations. Third, MM-GB/SA and FEP were used to identify fifteen non-standard tryptophan mutants at ProTx-II[W24] predicted in silico to have a at least a 1 kcal/mol gain in potency. These predicted potency gains are likely due to the displacement of high-energy waters as identified by the WaterMap algorithm for calculating the positions and thermodynamic properties of water molecules in protein binding sites. Our results expand the domain of applicability of FEP and set the stage for its prospective use in biologics drug discovery programs involving GMTs and NaV1.7. View Full-Text
Keywords: gating-modifier toxin; free-energy perturbation; sodium channel; drug discovery gating-modifier toxin; free-energy perturbation; sodium channel; drug discovery
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MDPI and ACS Style

Katz, D.; Sindhikara, D.; DiMattia, M.; Leffler, A.E. Potency-Enhancing Mutations of Gating Modifier Toxins for the Voltage-Gated Sodium Channel NaV1.7 Can Be Predicted Using Accurate Free-Energy Calculations. Toxins 2021, 13, 193. https://doi.org/10.3390/toxins13030193

AMA Style

Katz D, Sindhikara D, DiMattia M, Leffler AE. Potency-Enhancing Mutations of Gating Modifier Toxins for the Voltage-Gated Sodium Channel NaV1.7 Can Be Predicted Using Accurate Free-Energy Calculations. Toxins. 2021; 13(3):193. https://doi.org/10.3390/toxins13030193

Chicago/Turabian Style

Katz, Dana, Dan Sindhikara, Michael DiMattia, and Abba E. Leffler. 2021. "Potency-Enhancing Mutations of Gating Modifier Toxins for the Voltage-Gated Sodium Channel NaV1.7 Can Be Predicted Using Accurate Free-Energy Calculations" Toxins 13, no. 3: 193. https://doi.org/10.3390/toxins13030193

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