ISSN 1607-6729, Doklady Biochemistry and Biophysics, 2015, Vol. 461, pp. 106–109. © Pleiades Publishing, Ltd., 2015. Original Russian Text © I.E. Kasheverov, D.S. Kudryavtsev, I.A. Ivanov, M.N. Zhmak, A.O. Chugunov, V.M. Tabakmakher, E.A. Zelepuga, R.G. Efremov, V.I. Tsetlin, 2015, published in Doklady Akademii Nauk, 2015, Vol. 461, No. 4, pp. 476–479. 106 α-Conotoxins, comparatively short peptides of the venom of predatory marine mollusks of the genus Conus, are effective blockers of nicotinic acetylcholine receptors (nAChRs), which are actively used in studies of various nAChR types [1]. A significant advantage of conotoxins as compared to other known nAChR blockers—the polypeptide α-neurotoxins of snake venom—is an initially higher specificity with respect to certain subtypes of nicotinic receptors and possibil- ity to produce their various analogs by peptide synthe- sis. Such analogs are actively synthesized aiming to obtain highly specific ligands for each individual nAChR subtype mainly via introducing or replacing various amino acid residues in the structure of a selected α-conotoxin. For example, just a single mutation, [Ala10Leu], in α-conotoxin PnIA changes its specificity from nAChR subtype α3β2 to α7 [2], which is involved in pathogeneses of several diseases (Alzheimer’s disease, Parkinson’s disease, schizo- phrenia, etc.). Thus, the possibility to rationally design selective and potent α7 nAChR ligands is not only theoretically, but also practically important problem with a potential to become a breakthrough in molecular medicine. Numerous α-conotoxin PnIA analogs have been pro- duced to date, in particular, by Ala-scanning mutagenesis [3] or by introduction of various charged amino acid residues to different positions in the pep- tide molecule to obtain an analog more efficient and selective with respect to the α7 receptor subtype [4]. In the last work, we selected mutations by a classical computer modeling (docking of flexible ligand to rigid receptor) using the known crystal structures of mus- cle-type nAChR from the ray electric organ [5] and the complexes of acetylcholine-binding proteins (AChBPs) with several α-conotoxins [6, 7] or α-neurotoxin [8]. These water-soluble proteins, consisting of five identi- cal subunits, are structural homologs of the ligand- binding N-terminal domains in all nAChRs, being the closest to the homooligomeric α7 subtype. This approach has allowed us to produce several α-cono- toxin PnIA analogs with a high affinity and selectivity for the AChBPs from Lymnaea stagnalis or Aplysia cal- ifornica as well as an increased affinity for the human α7 nAChR. However, the best analog in the last case exhibited an affinity of approximately several hun- dreds of nanomoles per liter. This work continues the previous study and is aimed at designing a more efficient ligand for α7 nAChR using α-conotoxin PnIA. Here, we applied the computational protein surface topography (PST) technique, developed at the Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences [9], and for the first time used it to select the necessary mutations in conotoxins. The essence of this technique is in approximate representation of the structures of small peptides as a sphere and the physi- cochemical properties (charges and hydrophobicity) over their surface as projection maps, similar to the map of the Earth surface, which gave the algorithm its name. The group comparative analysis of bioactive peptides with the help of such maps makes it possible to detect the fine specific structure–function features in a set of molecules close in their structures and prop- erties as well as to find out their correlations with pep- tide activities towards certain targets. Availability of numerous earlier produced α-conotoxin PnIA ana- logs with determined activities (together with the data on the other structurally similar α-conotoxins) gave us the hope that such a group analysis would be fruitful and reveal the surface regions in molecules requiring Rational Design of New Ligands for Nicotinic Receptors on the Basis of α-Conotoxin PnIA I. E. Kasheverov a , D. S. Kudryavtsev a , I. A. Ivanov a , M. N. Zhmak a , A. O. Chugunov a , V. M. Tabakmakher b , E. A. Zelepuga b , R. G. Efremov a, c , and Corresponding Member of the RAS V. I. Tsetlin a Received December 2, 2014 DOI: 10.1134/S1607672915020118 a Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997 Russia e-mail: shak_ever@yahoo.com b Elyakov Pacific Institute of Bioorganic Chemistry, Far East Branch, Russian Academy of Sciences, Vladivostok, 690022 Russia c Higher School of Economics, Moscow, 101000 Russia BIOCHEMISTRY, BIOPHYSICS AND MOLECULAR BIOLOGY