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

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

Journal

Journal of Chemical Information and Modeling
ISSN: 1549-960X , E-ISSN: 1549-9596

Output data

Year: 2023, Volume: 63, Number: 4, Pages: 1239-1248 Pages count : 10 DOI: 10.1021/acs.jcim.2c01212

Authors

Losev Timofey V. ^1,2,3 , Gerasimov Igor S. ^4,3 , Panova Maria V. ³ , Lisov Alexey A. ³ , Abdyusheva Yana R. ^3,5 , Rusina Polina V. ³ , Zaletskaya Eugenia ^3,5 , Stroganov Oleg V. ⁶ , Medvedev Michael G. ³ , Novikov Fedor N. ^3,5

Affiliations

1	A.N. Nesmeyanov Institute of Organoelement Compounds of Russian Academy of Sciences, Vavilov Str. 28, 119991 Moscow, Russian Federation
2	Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russian Federation
3	N.D. Zelinsky Institute of Organic Chemistry of Russian Academy of Sciences, Leninsky prospect 47, 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

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.

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. V.63. N4. P.1239-1248. DOI: 10.1021/acs.jcim.2c01212 WOS Scopus OpenAlex

≡ Web of science:	WOS:000932628500001
≡ Scopus:	2-s2.0-85148002010
≡ OpenAlex:	W4319879430