SQM/COSMO Scoring Function: Reliable Quantum‐Mechanical Tool for Sampling and Ranking in Structure‐Based Drug Design

Pecina, Adam; Eyrilmez, Saltuk M.; Köprülüoğlu, Cemal; Miriyala, Vijay Madhav; Lepšı́k, Martin; Fanfrlík, Jindřich; Řezáč, Jan; Hobza, Pavel

doi:10.1002/cplu.202000120

Cited by 18 publications

(11 citation statements)

References 200 publications

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“…The models were build form the SAM (crystallographic ligand) manually and optimized at the AMBER 16 level prior the SQM energy calculations. TO507 had considerably more favorable (negative) binding 'free' energy (ΔG'int) 21,22 than SAH (-40.3 and -33.5 kcal mol-1, respectively). The contribution of single amino acids of SARS-CoV-2 nsp14 methyltransferase to the binding (ΔΔG'int) was studied by a virtual glycine scan.…”

Section: Molecular Modelingmentioning

confidence: 99%

“…The obtained structures were utilized for energy calculations. The binding 'free' energies [20][21][22] were computed at the PM6-D3H4X/COSMO2 [23][24][25] level of theory using MOPAC2016 26 and Cuby4 14,15 software. The contribution of the amino acids in the active site to the binding was examined by a "virtual glycine scanning".…”

Section: Molecular Modelingmentioning

confidence: 99%

“…20,21 First, the silyl-protecting group attached at the 5′-position was selectively removed by treatment with trichloroacetic acid affording nucleoside 2 in 72 % yield. 22 Activation of the 5′hydroxy group of the compound 2 with MsCl in the presence of Et3N allowed to introduce an aminoacid moiety by nucleophilic substitution with freshly prepared protected L-homocysteine salt 23,24 yielding SAH analogue 3 (82 % after two steps). This key intermediate 3 was then subjected to crosscoupling reactions to attach hetaryl and aryl substituents through various linkers.…”

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confidence: 99%

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The Structure-Based Design of SARS-CoV-2 nsp14 Methyltransferase Ligands Yields Nanomolar Inhibitors

Otava

Šála

et al. 2021

ACS Infect. Dis.

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COVID-19, caused by the SARS-CoV-2 virus, is responsible for a global pandemic that has paralyzed the normal life in many countries around the globe. Therefore, the preparation of both effective vaccines and potential therapeutics has become a major research priority in the biotechnology sector. Both viral proteins and selected host factors are important targets for the treatment of this disease. Suitable targets for antiviral therapy include i.a. viral methyltransferases, which allow the viral mRNA to be efficiently translated and protect the viral RNA from the innate immune system. In this study, we have focused on the structure-based design of the inhibitors of one of the two SARS-CoV-2 methyltransferases, nsp14. This methyltransferase catalyzes the transfer of the methyl group from S-adenosyl-L-methionine (SAM) to cap the guanosine triphosphate moiety of the newly synthesized viral RNA, yielding the methylated capped RNA and S-adenosyl-L-homocysteine (SAH). The crystal structure of SARS-CoV-2 nsp14 is unknown; we have taken advantage of its high homology to SARS-CoV nsp14 and prepared its homology model, which has allowed us to identify novel SAH derivatives modified at the adenine nucleobase as inhibitors of this important viral target.We have synthesized and tested the designed compounds in vitro and shown that these derivatives exert unprecedented inhibitory activity against this crucial enzyme. The docking studies nicely explain the contribution of an aromatic part attached by a linker to the position 7 of the 7-deaza analogues of SAH. Our results will serve as an important source of information for the subsequent development of new antivirals to combat COVID-19. File list (2) download file view on ChemRxiv nsp14_chemRxiv_Tomas.pdf (1.29 MiB) download file view on ChemRxiv chemRxiv_Supporting_final.pdf (4.16 MiB) The structure-based design of SARS-CoV-2 nsp14 methyltransferase ligands yields nanomolar

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Section: Molecular Modelingmentioning

confidence: 99%

Section: Molecular Modelingmentioning

confidence: 99%

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confidence: 99%

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The Structure-Based Design of SARS-CoV-2 nsp14 Methyltransferase Ligands Yields Nanomolar Inhibitors

Otava

Šála

et al. 2021

ACS Infect. Dis.

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“…The position of the inhibitor, water molecules, and residues within 4 Å were optimized in AMBER 14 implying the IGB7 implicit solvent model. The gas-phase interaction energies were computed as the energy difference between the energy of the complex and of its constituent parts (i.e., protein, ligand, and bridging water molecules) [34][35][36] at the PM6-D3H4X [37,38] level of theory using MOPAC2016 [39] and Cuby4 [40,41] software. "Free" energies refer to the sums of gas phase energies and solvation free energies.…”

Section: Structural Analysis Of Pimodivir Binding To Pb2 Variantsmentioning

confidence: 99%

Structural and Thermodynamic Analysis of the Resistance Development to Pimodivir (VX-787), the Clinical Inhibitor of Cap Binding to PB2 Subunit of Influenza A Polymerase

et al. 2021

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Influenza A virus (IAV) encodes a polymerase composed of three subunits: PA, with endonuclease activity, PB1 with polymerase activity and PB2 with host RNA five-prime cap binding site. Their cooperation and stepwise activation include a process called cap-snatching, which is a crucial step in the IAV life cycle. Reproduction of IAV can be blocked by disrupting the interaction between the PB2 domain and the five-prime cap. An inhibitor of this interaction called pimodivir (VX-787) recently entered the third phase of clinical trial; however, several mutations in PB2 that cause resistance to pimodivir were observed. First major mutation, F404Y, causing resistance was identified during preclinical testing, next the mutation M431I was identified in patients during the second phase of clinical trials. The mutation H357N was identified during testing of IAV strains at Centers for Disease Control and Prevention. We set out to provide a structural and thermodynamic analysis of the interactions between cap-binding domain of PB2 wild-type and PB2 variants bearing these mutations and pimodivir. Here we present four crystal structures of PB2-WT, PB2-F404Y, PB2-M431I and PB2-H357N in complex with pimodivir. We have thermodynamically analysed all PB2 variants and proposed the effect of these mutations on thermodynamic parameters of these interactions and pimodivir resistance development. These data will contribute to understanding the effect of these missense mutations to the resistance development and help to design next generation inhibitors.

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“…The thermodynamic model, COSMOSPACE, 23 leverages σ-profiles for all system components to determine chemical potentials, which are then used to determine component/mixture properties. COSMO-RS only requires DFT calculations, and not experimental data, for each new molecule and has been widely applied in solvent design, 24 drug design, 25 and surfactant systems. 26 Despite the success and broad application of COSMO-RS, challenges exist for predicting the properties of long-chain flexible bioproduct molecules (e.g., fatty acids, lipid-derived species, and waxes).…”

Section: Introductionmentioning

confidence: 99%

Adaptive Conformer Sampling for Property Prediction Using the Conductor-like Screening Model for Real Solvents

Maravelias

Lehn

2022

Ind. Eng. Chem. Res.

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The valorization of lignocellulose-derived bioproducts requires effective separation from excessive water. Liquid−liquid extraction is a promising low-energy separation technology, but effective extraction requires solvent selection based on the thermodynamic properties of the bioproduct and solvent components. We propose a computational framework for predicting such properties by developing an adaptive conformer selection approach for use with COSMO-RS (conductor-like screening model for real solvents) calculations. In this framework, molecular dynamics simulations are used to generate many molecular structures (conformers) at representative temperatures in varying solvent environments. Conformers are then clustered based on structural metrics in a low-dimensional space and selected using a mixed-integer quadratic programming problem to iteratively insert a sampled conformer. At each iteration, we determine bioproduct properties using COSMO-RS. We demonstrate the capability of the proposed framework on representative bioproducts to show convergence of the adaptive sampling toward experimentally measured properties with fewer calculations than required by random conformer sampling, enabling the improved screening of solvent systems for liquid-phase separation.

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SQM/COSMO Scoring Function: Reliable Quantum‐Mechanical Tool for Sampling and Ranking in Structure‐Based Drug Design

Abstract: Recently, SQM/COSMO was effectively applied in a proof-ofconcept study of enrichment in virtual screening. Due to its superior performance, feasibility and chemical generality, we propose the SQM/COSMO approach as an efficient tool in structure-based drug design.

Cited by 18 publications

References 200 publications

The Structure-Based Design of SARS-CoV-2 nsp14 Methyltransferase Ligands Yields Nanomolar Inhibitors

The Structure-Based Design of SARS-CoV-2 nsp14 Methyltransferase Ligands Yields Nanomolar Inhibitors

Structural and Thermodynamic Analysis of the Resistance Development to Pimodivir (VX-787), the Clinical Inhibitor of Cap Binding to PB2 Subunit of Influenza A Polymerase

Adaptive Conformer Sampling for Property Prediction Using the Conductor-like Screening Model for Real Solvents

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