Structure‐ and Interaction‐Based Design of Anti‐SARS‐CoV‐2 Aptamers

• Published in: Chemistry : a European journal Vol. 28; no. 12; pp. e202104481 - n/a
• Main Authors: Mironov, Vladimir, Shchugoreva, Irina A., Artyushenko, Polina V., Morozov, Dmitry, Borbone, Nicola, Oliviero, Giorgia, Zamay, Tatiana N., Moryachkov, Roman V., Kolovskaya, Olga S., Lukyanenko, Kirill A., Song, Yangling, Merkuleva, Iuliia A., Zabluda, Vladimir N., Peters, Georgy, Koroleva, Lyudmila S., Veprintsev, Dmitry V., Glazyrin, Yury E., Volosnikova, Ekaterina A., Belenkaya, Svetlana V., Esina, Tatiana I., Isaeva, Anastasiya A., Nesmeyanova, Valentina S., Shanshin, Daniil V., Berlina, Anna N., Komova, Nadezhda S., Svetlichnyi, Valery A., Silnikov, Vladimir N., Shcherbakov, Dmitriy N., Zamay, Galina S., Zamay, Sergey S., Smolyarova, Tatyana, Tikhonova, Elena P., Chen, Kelvin H. -C., Jeng, U-Ser, Condorelli, Gerolama, de Franciscis, Vittorio, Groenhof, Gerrit, Yang, Chaoyong, Moskovsky, Alexander A., Fedorov, Dmitri G., Tomilin, Felix N., Tan, Weihong, Alexeev, Yuri, Berezovski, Maxim V., Kichkailo, Anna S
• Format: Journal Article
• Language: English
• Published: Germany Wiley 24.02.2022; Wiley Subscription Services, Inc; Wiley Blackwell (John Wiley & Sons); John Wiley and Sons Inc
• Subjects: 60 APPLIED LIFE SCIENCES; Affinity; Aptamers; aptamers, fragment molecular orbitals method, molecular dynamics, SARS-CoV-2, SAXS; Aptamers, Nucleotide; Aptamers, Nucleotide - chemistry; Binding; Chemistry; Computer applications; COVID-19; Cytometry; Design; DNA probes; Drug development; Fluorescence; Fluorescence polarization; fragment molecular orbitals method; Humans; Iterative methods; laskennallinen kemia; lääkesuunnittelu; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; Molecular modelling; Molecular structure; molekyylidynamiikka; Mutagenesis; Nucleic acids; oligonukleotidit; proteiinit; Protein structure; Proteins; SARS-CoV-2; SARS-CoV-2, белки; SARS-CoV-2-virus; SAXS; SELEX Aptamer Technique; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus; Spike protein; Tertiary structure; Three dimensional models; дизайн аптамеров; fragment molecular orbitals method; SARS-CoV-2; molecular dynamics; aptamers; SAXS
• ISSN: 0947-6539; 1521-3765; 1521-3765
• DOI: 10.1002/chem.202104481

Aptamer selection against novel infections is a complicated and time‐consuming approach. Synergy can be achieved by using computational methods together with experimental procedures. This study aims to develop a reliable methodology for a rational aptamer in silico et vitro design. The new approach combines multiple steps: (1) Molecular design, based on screening in a DNA aptamer library and directed mutagenesis to fit the protein tertiary structure; (2) 3D molecular modeling of the target; (3) Molecular docking of an aptamer with the protein; (4) Molecular dynamics (MD) simulations of the complexes; (5) Quantum‐mechanical (QM) evaluation of the interactions between aptamer and target with further analysis; (6) Experimental verification at each cycle for structure and binding affinity by using small‐angle X‐ray scattering, cytometry, and fluorescence polarization. By using a new iterative design procedure, structure‐ and interaction‐based drug design (SIBDD), a highly specific aptamer to the receptor‐binding domain of the SARS‐CoV‐2 spike protein, was developed and validated. The SIBDD approach enhances speed of the high‐affinity aptamers development from scratch, using a target protein structure. The method could be used to improve existing aptamers for stronger binding. This approach brings to an advanced level the development of novel affinity probes, functional nucleic acids. It offers a blueprint for the straightforward design of targeting molecules for new pathogen agents and emerging variants. Applying computational methods together with experimental procedures can speed up aptamer design. By using a new iterative design procedure, structure and interaction‐based drug design (SIBDD), a highly specific aptamer to the receptor‐binding domain of the SARS‐CoV‐2 spike protein, was designed and validated. The approach combines molecular dynamics with quantum chemistry to estimate binding affinity in silico with in vitro verification.