Journal of Chemical Information and Modeling, volume 63, issue 4, pages 1239-1248

Quantum Mechanical-Cluster Approach to Solve the Bioisosteric Replacement Problem in Drug Design

Losev Timofey V. ^{1, 2, 3}

Gerasimov Igor S. ^{1, 4}

Panova Maria V. ¹

Lisov Alexey A. ¹

Abdyusheva Yana R. ^{1, 5}

Rusina Polina V. ¹

Zaletskaya Eugenia ^{1, 5}

Stroganov Oleg V. ⁶

Medvedev Michael G. ¹

Novikov Fedor N. ^{1, 5}

Hide authors affiliations Show authors affiliations: 6 affiliations

N.D. Zelinsky Institute of Organic Chemistry of Russian Academy of Sciences, Leninsky prospect 47, 119991 Moscow, Russian Federation |

Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russian Federation |

A.N. Nesmeyanov Institute of Organoelement Compounds of Russian Academy of Sciences, Vavilov Str. 28, 119991 Moscow, Russian Federation |

⁴

Department of Chemistry, Kyungpook National University, Daegu 41566, South Korea |

⁵

National Research University Higher School of Economics, Myasnitskaya Street 20, 101000 Moscow, Russian Federation |

⁶

BioMolTech Corp., 226 York Mills Rd, Toronto, Ontario M2L 1L1, Canada |

Publication type: Journal Article

Publication date: 2023-02-10

American Chemical Society (ACS)

Journal: Journal of Chemical Information and Modeling

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Impact factor: 5.6

ISSN: 15499596, 1549960X

DOI: 10.1021/acs.jcim.2c01212

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General Chemistry

Computer Science Applications

General Chemical Engineering

Library and Information Sciences

Abstract

Bioisosteres are molecules that differ in substituents but still have very similar shapes. Bioisosteric replacements are ubiquitous in modern drug design, where they are used to alter metabolism, change bioavailability, or modify activity of the lead compound. Prediction of relative affinities of bioisosteres with computational methods is a long-standing task; however, the very shape closeness makes bioisosteric substitutions almost intractable for computational methods, which use standard force fields. Here, we design a quantum mechanical (QM)-cluster approach based on the GFN2-xTB semi-empirical quantum-chemical method and apply it to a set of H → F bioisosteric replacements. The proposed methodology enables advanced prediction of biological activity change upon bioisosteric substitution of −H with −F, with the standard deviation of 0.60 kcal/mol, surpassing the ChemPLP scoring function (0.83 kcal/mol), and making QM-based ΔΔG estimation comparable to ∼0.42 kcal/mol standard deviation of in vitro experiment. The speed of the method and lack of tunable parameters makes it affordable in current drug research.

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Losev T. V. et al. Quantum Mechanical-Cluster Approach to Solve the Bioisosteric Replacement Problem in Drug Design // Journal of Chemical Information and Modeling. 2023. Vol. 63. No. 4. pp. 1239-1248.

GOST all authors (up to 50) Copy

Losev T. V., Gerasimov I. S., Panova M. V., Lisov A. A., Abdyusheva Y. R., Rusina P. V., Zaletskaya E., Stroganov O. V., Medvedev M. G., Novikov F. N. Quantum Mechanical-Cluster Approach to Solve the Bioisosteric Replacement Problem in Drug Design // Journal of Chemical Information and Modeling. 2023. Vol. 63. No. 4. pp. 1239-1248.

RIS |

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TY - JOUR

DO - 10.1021/acs.jcim.2c01212

UR - https://doi.org/10.1021%2Facs.jcim.2c01212

TI - Quantum Mechanical-Cluster Approach to Solve the Bioisosteric Replacement Problem in Drug Design

T2 - Journal of Chemical Information and Modeling

AU - Losev, Timofey V.

AU - Gerasimov, Igor S.

AU - Panova, Maria V.

AU - Lisov, Alexey A.

AU - Abdyusheva, Yana R.

AU - Rusina, Polina V.

AU - Zaletskaya, Eugenia

AU - Stroganov, Oleg V.

AU - Medvedev, Michael G.

AU - Novikov, Fedor N.

PY - 2023

DA - 2023/02/10 00:00:00

PB - American Chemical Society (ACS)

SP - 1239-1248

IS - 4

VL - 63

SN - 1549-9596

SN - 1549-960X

ER -

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@article{2023_Losev,

author = {Timofey V. Losev and Igor S. Gerasimov and Maria V. Panova and Alexey A. Lisov and Yana R. Abdyusheva and Polina V. Rusina and Eugenia Zaletskaya and Oleg V. Stroganov and Michael G. Medvedev and Fedor N. Novikov},

title = {Quantum Mechanical-Cluster Approach to Solve the Bioisosteric Replacement Problem in Drug Design},

journal = {Journal of Chemical Information and Modeling},

year = {2023},

volume = {63},

publisher = {American Chemical Society (ACS)},

month = {feb},

url = {https://doi.org/10.1021%2Facs.jcim.2c01212},

number = {4},

pages = {1239--1248},

doi = {10.1021/acs.jcim.2c01212}

}

MLA

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Losev, Timofey V., et al. “Quantum Mechanical-Cluster Approach to Solve the Bioisosteric Replacement Problem in Drug Design.” Journal of Chemical Information and Modeling, vol. 63, no. 4, Feb. 2023, pp. 1239-1248. https://doi.org/10.1021%2Facs.jcim.2c01212.

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Publisher

American Chemical Society (ACS)

Journal

Journal of Chemical Information and Modeling

Quartile SCImago

Quartile WOS

Impact factor

5.6

ISSN

15499596 (Print)
1549960X (Electronic)

Labs

Theoretical Chemistry Group of the IOH RAS

Profiles

Medvedev, Michael G