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Article

Potency- and Selectivity-Enhancing Mutations of Conotoxins for Nicotinic Acetylcholine Receptors Can Be Predicted Using Accurate Free-Energy Calculations

1
Schrödinger, Inc., 120 West 45th St., New York, NY 10036, USA
2
D.E. Shaw India Private Ltd., Hyderabad 500096, India
*
Author to whom correspondence should be addressed.
Current address: Merck and Co., Inc., Kenilworth, NJ 07033, USA.
Academic Editors: Susana P Gaudencio and Florbela Pereira
Mar. Drugs 2021, 19(7), 367; https://doi.org/10.3390/md19070367
Received: 27 May 2021 / Revised: 18 June 2021 / Accepted: 22 June 2021 / Published: 25 June 2021
(This article belongs to the Special Issue Marine Drug Discovery through Computer-Aided Approaches)
Nicotinic acetylcholine receptor (nAChR) subtypes are key drug targets, but it is challenging to pharmacologically differentiate between them because of their highly similar sequence identities. Furthermore, α-conotoxins (α-CTXs) are naturally selective and competitive antagonists for nAChRs and hold great potential for treating nAChR disorders. Identifying selectivity-enhancing mutations is the chief aim of most α-CTX mutagenesis studies, although doing so with traditional docking methods is difficult due to the lack of α-CTX/nAChR crystal structures. Here, we use homology modeling to predict the structures of α-CTXs bound to two nearly identical nAChR subtypes, α3β2 and α3β4, and use free-energy perturbation (FEP) to re-predict the relative potency and selectivity of α-CTX mutants at these subtypes. First, we use three available crystal structures of the nAChR homologue, acetylcholine-binding protein (AChBP), and re-predict the relative affinities of twenty point mutations made to the α-CTXs LvIA, LsIA, and GIC, with an overall root mean square error (RMSE) of 1.08 ± 0.15 kcal/mol and an R2 of 0.62, equivalent to experimental uncertainty. We then use AChBP as a template for α3β2 and α3β4 nAChR homology models bound to the α-CTX LvIA and re-predict the potencies of eleven point mutations at both subtypes, with an overall RMSE of 0.85 ± 0.08 kcal/mol and an R2 of 0.49. This is significantly better than the widely used molecular mechanics—generalized born/surface area (MM-GB/SA) method, which gives an RMSE of 1.96 ± 0.24 kcal/mol and an R2 of 0.06 on the same test set. Next, we demonstrate that FEP accurately classifies α3β2 nAChR selective LvIA mutants while MM-GB/SA does not. Finally, we use FEP to perform an exhaustive amino acid mutational scan of LvIA and predict fifty-two mutations of LvIA to have greater than 100X selectivity for the α3β2 nAChR. Our results demonstrate the FEP is well-suited to accurately predict potency- and selectivity-enhancing mutations of α-CTXs for nAChRs and to identify alternative strategies for developing selective α-CTXs. View Full-Text
Keywords: conotoxin; nicotinic acetylcholine receptor; selectivity; free-energy perturbation conotoxin; nicotinic acetylcholine receptor; selectivity; free-energy perturbation
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MDPI and ACS Style

Katz, D.; DiMattia, M.A.; Sindhikara, D.; Li, H.; Abraham, N.; Leffler, A.E. Potency- and Selectivity-Enhancing Mutations of Conotoxins for Nicotinic Acetylcholine Receptors Can Be Predicted Using Accurate Free-Energy Calculations. Mar. Drugs 2021, 19, 367. https://doi.org/10.3390/md19070367

AMA Style

Katz D, DiMattia MA, Sindhikara D, Li H, Abraham N, Leffler AE. Potency- and Selectivity-Enhancing Mutations of Conotoxins for Nicotinic Acetylcholine Receptors Can Be Predicted Using Accurate Free-Energy Calculations. Marine Drugs. 2021; 19(7):367. https://doi.org/10.3390/md19070367

Chicago/Turabian Style

Katz, Dana, Michael A. DiMattia, Dan Sindhikara, Hubert Li, Nikita Abraham, and Abba E. Leffler 2021. "Potency- and Selectivity-Enhancing Mutations of Conotoxins for Nicotinic Acetylcholine Receptors Can Be Predicted Using Accurate Free-Energy Calculations" Marine Drugs 19, no. 7: 367. https://doi.org/10.3390/md19070367

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