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Experimental Quantum Chemistry: A Hammett-inspired Fingerprinting of Substituent Effects.

ABSTRACT: The quantum mechanically calculable Q descriptor is shown to be a potent quantifier of chemical reactivity in complex molecules - it shows a strong correlation to experimentally derived field effects in non-aromatic substrates and Hammett σ_m and σ_p parameters. Models for predicting substituent effects from Q are presented and applied, including on the elusive pentazolyl substituent. The presented approach enables fast computational estimation of substituent effects, and, in extension, medium-throughput screening of molecules and compound design. An experimental dataset is suggested as a candidate benchmark for aiding the general development and comparison of electronic structure analyses. It is here used to evaluate the experimental quantum chemistry (EQC) framework for chemical bonding analysis in larger molecules.

SUBMITTER: Sessa F

PROVIDER: S-EPMC8049055 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Experimental Quantum Chemistry: A Hammett-inspired Fingerprinting of Substituent Effects.

Sessa Francesco F Olsson Martina M Söderberg Fredrik F Wang Fang F Rahm Martin M

Chemphyschem : a European journal of chemical physics and physical chemistry 20210222 6

The quantum mechanically calculable Q descriptor is shown to be a potent quantifier of chemical reactivity in complex molecules - it shows a strong correlation to experimentally derived field effects in non-aromatic substrates and Hammett σ<sub>m</sub> and σ<sub>p</sub> parameters. Models for predicting substituent effects from Q are presented and applied, including on the elusive pentazolyl substituent. The presented approach enables fast computational estimation of substituent effects, and, in ...[more]

PMID: 33502056

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Project description:The COVID-19 pandemic has accelerated the need to identify new antiviral therapeutics at pace, including through drug repurposing. We employed a Quadratic Unbounded Binary Optimization (QUBO) model, to search for compounds similar to Remdesivir, the first antiviral against SARS-CoV-2 approved for human use, using a quantum-inspired device. We modelled Remdesivir and compounds present in the DrugBank database as graphs, established the optimal parameters in our algorithm and resolved the Maximum Weighted Independent Set problem within the conflict graph generated. We also employed a traditional Tanimoto fingerprint model. The two methods yielded different lists of lead compounds, with some overlap. While GS-6620 was the top compound predicted by both models, the QUBO model predicted BMS-986094 as second best. The Tanimoto model predicted different forms of cobalamin, also known as vitamin B12. We then determined the half maximal inhibitory concentration (IC50) values in cell culture models of SARS-CoV-2 infection and assessed cytotoxicity. We also demonstrated efficacy against several variants including SARS-CoV-2 Strain England 2 (England 02/2020/407073), B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta). Lastly, we employed an in vitro polymerization assay to demonstrate that these compounds directly inhibit the RNA-dependent RNA polymerase (RdRP) of SARS-CoV-2. Together, our data reveal that our QUBO model performs accurate comparisons (BMS-986094) that differed from those predicted by Tanimoto (different forms of vitamin B12); all compounds inhibited replication of SARS-CoV-2 via direct action on RdRP, with both models being useful. While Tanimoto may be employed when performing relatively small comparisons, QUBO is also accurate and may be well suited for very complex problems where computational resources may limit the number and/or complexity of possible combinations to evaluate. Our quantum-inspired screening method can therefore be employed in future searches for novel pharmacologic inhibitors, thus providing an approach for accelerating drug deployment.

Project description:Applicability of Hammett parameters (σ m and σ p ) was tested in extended π-systems in gas phase. Three different model graphene systems, viz. 5,5-graphene (GR), 3-B-5,5-graphene (3BGR), and 3-N-5,5-graphene (3NGR), were designed as extended π-systems, and interactions of various nitrobenzene derivatives (mainly m- and p-substituted together with some multiple substitutions) on such platforms were monitored using density functional theory (M06/cc-pVDZ, M06/cc-pVTZ, M06/sp-aug-cc-pVTZ) and Møller-Plesset second-order perturbation (MP2/cc-pV-DZ) theory. Offset face to face (OSFF) stackings were found to be the favored orientations, and reasonable correlations were found between binding energies (ΔE B) and the ∑|σ m | values of the substituted nitrobenzenes. It was proposed previously that |σ m | contains information about the substituents' polarizability and controls electrostatic and dispersion interactions. The combination of ∑|σ m | and molar refractivity (as ∑M r) or change in polarizability (Δα: with respect to benzene) of nitrobenzene derivatives generated statistically significant correlation with respect to ΔE B, thereby supporting the hypothesis related to the validity of |σ m | correlations. The |σ p | parameters also maintain similar correlations for the various p-substituted nitrobenzene derivatives together with several multiply-substituted nitrobenzene derivatives. The correlation properties in such cases are similar to the |σ m | cases, and the energy partition analysis for both the situations reveled importance of electrostatic and dispersion contributions in such interactions. The applicability of Hammett parameters was observed previously on the restricted parallel face to face orientation of benzene···substituted benzene systems, and the present results show that such an idea could be used to predict ΔE B values in OSFF orientations, if the scaffolds are designed in such a way that substituted benzene systems cannot escape their π-clouds.

Dataset Information

Experimental Quantum Chemistry: A Hammett-inspired Fingerprinting of Substituent Effects.

Publications

Experimental Quantum Chemistry: A Hammett-inspired Fingerprinting of Substituent Effects.

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