Proof of concept for poor inhibitor binding and efficient formation of covalent adducts of KRASG12Cand ARS compounds

Khrenova, Maria G.; Kulakova, A. M.; Nemukhin, Alexander V.

doi:10.1039/d0ob00071j

Cited by 22 publications

(21 citation statements)

References 55 publications

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“…For different NDM-1 with cpd5 complexes, we observe similar behavior of the Laplacian of electron density in the interatomic region: a flat area with the electron density deconcentration, with ∇ 2 ρ(r) being around 0.05 a.u. Such regions are attributed to the presence of the substrate activation effect that was previously demonstrated on the 2D maps of ∇ 2 ρ(r) [42,43,69,72]. From this viewpoint, the boron atom is activated in all presented MD frames.…”

Section: Imipenem and Boronic Acid Inhibitor Cpd5 In Water Solution And In The Active Site Of Ndm-1mentioning

confidence: 53%

“…It means that not all ES complexes (frames along the MD trajectory) correspond to the reactive species. The fraction with the larger f+ values demonstrates the substrate activation in the active site of the enzyme discussed in Refs [59,69]. The Gibbs energy profile for the nucleophilic attack step was calculated using the umbrella sampling technique (Figure 5).…”

Section: Imipenem and Boronic Acid Inhibitor Cpd5 In Water Solution And In The Active Site Of Ndm-1mentioning

confidence: 99%

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Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling

Krivitskaya

Khrenova

2021

Molecules

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Boronic acids are prospective compounds in inhibition of metallo-β-lactamases as they form covalent adducts with the catalytic hydroxide anion in the enzymatic active site upon binding. We compare this chemical reaction in the active site of the New Delhi metallo-β-lactamase (NDM-1) with the hydrolysis of the antibacterial drug imipenem. The nucleophilic attack occurs with the energy barrier of 14 kcal/mol for imipenem and simultaneously upon binding a boronic acid inhibitor. A boron atom of an inhibitor exhibits stronger electrophilic properties than the carbonyl carbon atom of imipenem in a solution that is quantified by atomic Fukui indices. Upon forming the prereaction complex between NDM-1 and inhibitor, the lone electron pair of the nucleophile interacts with the vacant p-orbital of boron that facilitates the chemical reaction. We analyze a set of boronic acid compounds with the benzo[b]thiophene core complexed with the NDM-1 and propose quantitative structure-sroperty relationship (QSPR) equations that can predict IC50 values from the calculated descriptors of electron density. These relations are applied to classify other boronic acids with the same core found in the database of chemical compounds, PubChem, and proposed ourselves. We demonstrate that the IC50 values for all considered benzo[b]thiophene-containing boronic acid inhibitors are 30–70 μM.

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Section: Imipenem and Boronic Acid Inhibitor Cpd5 In Water Solution And In The Active Site Of Ndm-1mentioning

confidence: 53%

Section: Imipenem and Boronic Acid Inhibitor Cpd5 In Water Solution And In The Active Site Of Ndm-1mentioning

confidence: 99%

Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling

Krivitskaya

Khrenova

2021

Molecules

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“…Step 4 The spatial distributions of the Laplacian of the electron density, ∇ 2 ρ(r), were calculated at different frames of the QM/MM MD trajectory of the ES complex to discriminate reactive and nonreactive species. Previous works [24,30,31,42,43] demonstrate that this approach is a proper tool to visualize the substrate activation in nucleophilic reactions. In molecular systems, the areas of the local electronic charge concentration regions with ∇ 2 ρ(r) < 0 (electrophilic sites) and electronic charge depletion areas with ∇ 2 ρ(r) > 0 (nucleophilic sites) are formed.…”

Section: Models and Methodsmentioning

confidence: 99%

Two Sides of Quantum-Based Modeling of Enzyme-Catalyzed Reactions: Mechanistic and Electronic Structure Aspects of the Hydrolysis by Glutamate Carboxypeptidase

2021

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We report the results of a computational study of the hydrolysis reaction mechanism of N-acetyl-l-aspartyl-l-glutamate (NAAG) catalyzed by glutamate carboxypeptidase II. Analysis of both mechanistic and electronic structure aspects of this multistep reaction is in the focus of this work. In these simulations, model systems are constructed using the relevant crystal structure of the mutated inactive enzyme. After selection of reaction coordinates, the Gibbs energy profiles of elementary steps of the reaction are computed using molecular dynamics simulations with ab initio type QM/MM potentials (QM/MM MD). Energies and forces in the large QM subsystem are estimated in the DFT(PBE0-D3/6-31G**) approximation. The established mechanism includes four elementary steps with the activation energy barriers not exceeding 7 kcal/mol. The models explain the role of point mutations in the enzyme observed in the experimental kinetic studies; namely, the Tyr552Ile substitution disturbs the “oxyanion hole”, and the Glu424Gln replacement increases the distance of the nucleophilic attack. Both issues diminish the substrate activation in the enzyme active site. To quantify the substrate activation, we apply the QTAIM-based approaches and the NBO analysis of dynamic features of the corresponding enzyme-substrate complexes. Analysis of the 2D Laplacian of electron density maps allows one to define structures with the electron density deconcentration on the substrate carbon atom, i.e., at the electrophilic site of reactants. The similar electronic structure element in the NBO approach is a lone vacancy on the carbonyl carbon atom in the reactive species. The electronic structure patterns revealed in the NBO and QTAIM-based analyses consistently clarify the reactivity issues in this system.

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“…The Laplacian of the electron density,  2 (r), 36,54 was calculated at different frames of the QM/MM MD trajectory of the ES complex to discriminate reactive and nonreactive species. Previous works 37,38,55,56 demonstrate that this approach is a proper tool to visualize the activation in the nucleophilic attack step. In the molecular systems the areas of the local electronic charge concentration regions with  2 (r) < 0 (electrophilic sites) and electronic charge depletion areas with  2 (r)>0 (nucleophilic sites) are formed.…”

Section: Methodsmentioning

confidence: 99%

Molecular Mechanism of Light-Induced Acceleration of the Adenosine Triphosphate Conversion to the Cyclic Adenosine Monophosphate Catalyzed by the Photoactivated Adenylyl Cyclase bPAC

Nemukhin

Khrenova²,

Kulakova³

2020

Preprint

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We report the first computational characterization of an optogenetic system composed of two photosensing BLUF (blue light sensor using flavin adenine dinucleotide) domains and two catalytic adenylyl cyclase (AC) domains. Conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP) and pyrophosphate (PPi) catalyzed by ACs coupled with excitation in photosensing domains has emerged in the focus of modern optogenetic applications because of the request in photoregulated enzymes to modulate cellular concentrations of signaling messengers. The photoactivated adenylyl cyclase from the soil bacterium Beggiatoa sp. (bPAC) is an important model showing considerable increase of the ATP to cAMP conversion rate in the catalytic domain after the illumination of the BLUF domain. The 1 μs classical molecular dynamics simulations reveal that the activation of the BLUF domain leading to tautomerization of Gln49 in the chromophore binding pocket results in switching of position of the side chain of Arg278 in the active site of AC. Allosteric signal transmission pathways between Gln49 from BLUF and Arg278 from AC were revealed by the dynamical network analysis. The Gibbs energy profiles of the ATP → cAMP + PPi reaction computed using QM(DFT(ωB97X-D3/6-31G**))/MM(CHARMM) molecular dynamics simulations for both Arg278 conformations in AC clarify the reaction mechanism. In the light-activated system, the corresponding arginine conformation stabilizes the pentacoordinated phosphorus of the α-phosphate group in the transition state, thus lowering the activation energy. Simulations of the bPAC system with the Tyr7Phe replacement in BLUF demonstrate occurrence of both arginine conformations in an equal ratio, explaining the experimentally observed intermediate catalytic activity of the bPAC-Y7F variant as compared with the dark and light states of the wild type bPAC.

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Proof of concept for poor inhibitor binding and efficient formation of covalent adducts of KRAS^G12Cand ARS compounds

Abstract: Comprehensive molecular modeling and kinetic analysis reveal a novel mechanism of the inhibition of the oncogenic mutant of the “undruggable” KRAS protein.

Cited by 22 publications

References 55 publications

Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling

Boronic Acids as Prospective Inhibitors of Metallo-β-Lactamases: Efficient Chemical Reaction in the Enzymatic Active Site Revealed by Molecular Modeling

Two Sides of Quantum-Based Modeling of Enzyme-Catalyzed Reactions: Mechanistic and Electronic Structure Aspects of the Hydrolysis by Glutamate Carboxypeptidase

Molecular Mechanism of Light-Induced Acceleration of the Adenosine Triphosphate Conversion to the Cyclic Adenosine Monophosphate Catalyzed by the Photoactivated Adenylyl Cyclase bPAC

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