Prediction of Binding Pose and Affinity of Nelfinavir, a SARS-CoV-2 Main Protease Repositioned Drug, by Combining Docking, Molecular Dynamics, and Fragment Molecular Orbital Calculations.

Shigenori Tanaka, Yusuke Kawashima, Kaori Fukuzawa, Yuji Mochizuki, Teruki Honma, Yuma Handa, Koji Okuwaki, Ryo Hatada, Yuto Komeiji, Takayuki Furuishi, Etsuo Yonemochi

Journal: The journal of physical chemistry. B 2024;128(10):2249-2265

PMID: 38437183

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Abstract

A novel drug design procedure is described targeting the Main protease (Mpro) of the SARS-CoV-2 virus. The procedure combines molecular docking, molecular dynamics (MD), and fragment molecular orbital (FMO) calculations. The binding structure and properties of Mpro were predicted for Nelfinavir (NFV), which had been identified as a candidate compound through drug repositioning, targeting Mpro. Several poses of the Mpro and NFV complexes were generated by docking, from which four docking poses were selected by scoring with FMO energy. Then, each pose was subjected to MD simulation, 100 snapshot structures were sampled from each of the generated MD trajectories, and the structures were evaluated by FMO calculations to rank the pose based on binding energy. Several residues were found to be important in ligand recognition, including Glu47, Asp48, Glu166, Asp187, and Gln189, all of which interacted strongly with NFV. Asn142 is presumably regarded to form hydrogen bonds or CH/π interaction with NFV; however, in the present calculation, their interactions were transient. Moreover, the -butyl group of NFV had no interaction with Mpro. Identifying such strong and weak interactions provides candidates for maintaining and substituting ligand functional groups and important suggestions for drug discovery using drug repositioning. Besides the interaction between NFV and the amino acid residues of Mpro, the desolvation effect of the binding pocket also affected the ranking order. A similar procedure of drug design was applied to Lopinavir, and the calculated interaction energy and experimental inhibitory activity value trends were consistent. Our approach provides a new guideline for structure-based drug design starting from a candidate compound whose complex crystal structure has not been obtained.

Address: Department of Physical Chemistry, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.; Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.; Department of Physical Chemistry, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.; Department of Chemistry and Research Center for Smart Molecules, Faculty of Science, Rikkyo University, 3-34-1 Nishi-ikebukuro, Toshima-ku, Tokyo 171-8501, Japan.; Department of Physical Chemistry, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.; Department of Chemistry and Research Center for Smart Molecules, Faculty of Science, Rikkyo University, 3-34-1 Nishi-ikebukuro, Toshima-ku, Tokyo 171-8501, Japan.; Department of Chemistry and Research Center for Smart Molecules, Faculty of Science, Rikkyo University, 3-34-1 Nishi-ikebukuro, Toshima-ku, Tokyo 171-8501, Japan.; Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan.; Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.; Department of Chemistry and Research Center for Smart Molecules, Faculty of Science, Rikkyo University, 3-34-1 Nishi-ikebukuro, Toshima-ku, Tokyo 171-8501, Japan.; Health and Medical Research Institute, AIST, Tsukuba Central 6, Tsukuba, Ibaraki 305-8566, Japan.; RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.; Graduate School of System Informatics, Department of Computational Science, Kobe University, 1-1 Rokkodai, Nada-ku, Kobe 657-8501, Japan.; RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.; Department of Physical Chemistry, School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.; Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.; Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University, 6-6-11 Aoba, Aramaki, Aoba-ku, Sendai 980-8579, Japan.

DOI: 10.1021/acs.jpcb.3c05564

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MeSH Terms: Humans, COVID-19, Ligands, Molecular Docking Simulation, Nelfinavir, SARS-CoV-2, Molecular Dynamics Simulation, Coronavirus 3C Proteases