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DFT studies of the ring-opening mechanism of SB-3CT, a potent inhibitor of matrix metalloproteinase 2.

ABSTRACT: SB-3CT is a 2-[(arylsulfonyl)methyl]thiirane that achieves potent inhibition, by a thiirane-opening mechanism, of the MMP2 and MMP9 zinc metalloproteases. The deprotonation mechanism for thiirane opening of SB-3CT and for the opening of its oxirane analogue, both relevant to the inhibition of MMP2, was investigated computationally using the acetate anion as the Brønsted base and in methanol and acetonitrile as solvents. The activation barriers for the reaction show a significant stereoelectronic effect. The lowest energy paths have the breaking C-H bond gauche to both sulfone oxygens and with this C-H bond anti to the breaking C-S bond of the thiirane. The calculated primary isotope effect agrees with experimental data.

SUBMITTER: Tao P

PROVIDER: S-EPMC2821186 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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DFT studies of the ring-opening mechanism of SB-3CT, a potent inhibitor of matrix metalloproteinase 2.

Tao Peng P Fisher Jed F JF Mobashery Shahriar S Schlegel H Bernhard HB

Organic letters 20090601 12

SB-3CT is a 2-[(arylsulfonyl)methyl]thiirane that achieves potent inhibition, by a thiirane-opening mechanism, of the MMP2 and MMP9 zinc metalloproteases. The deprotonation mechanism for thiirane opening of SB-3CT and for the opening of its oxirane analogue, both relevant to the inhibition of MMP2, was investigated computationally using the acetate anion as the Brønsted base and in methanol and acetonitrile as solvents. The activation barriers for the reaction show a significant stereoelectronic ...[more]

PMID: 19445474

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Project description:(4-Phenoxyphenylsulfonyl)methylthiirane (SB-3CT) is the selective inhibitor of matrix metalloproteinase 2 (MMP2). The inhibition mechanism of MMP2 by SB-3CT involves C-H deprotonation with concomitant opening of the three-membered heterocycle. In this study, the energetics of the deprotonation-induced ring-opening of (4-phenoxyphenylsulfinyl)methylthiirane, the sulfoxide analogue of SB-3CT, are examined computationally using DFT and QM/MM calculations. A model system, 2-(methylsulfinylmethyl)thiirane, is used to study the stereoelectronic and conformational effects of reaction barriers in methanol. For the model system in methanol solution (using the polarizable continuum model), the reaction barriers range from 17 to 23 kcal/mol with significant stereoelectronic effects. However, the lowest barriers of the (R,R) and (S,R) diastereomers are similar. Two diastereomers of the sulfoxide analogue of SB-3CT are studied in the active site of MMP2 by QM/MM methods with an accurate partial charge fitting procedure. The ring-opening reactions of these two diastereomers have similar reaction energetics. Both are exothermic from the reactant to the ring-opening product (thiolate). The protonation of the thiolate by a water molecule is endothermic in both cases. However, the deprotonation/ring-opening barriers in the MMP2 active site using QM/MM methods for the (R,R) and (S,R) inhibitions are quite different (23.3 and 28.5 kcal/mol, respectively). The TSs identified in QM/MM calculations were confirmed by vibrational frequency analysis and following the reaction path. The (R,R) diastereomer has a hydrogen bond between the sulfoxide oxygen and the backbone NH of Leu191, while the (S,R) has a hydrogen bond between the sulfoxide oxygen and a water molecule. The dissimilar strengths of these hydrogen bonds as well as minor differences in the TS structures contribute to the difference between the barriers. Compared to SB-3CT, both diastereomers of the sulfoxide analogue have higher reaction barriers and have less exothermic reaction energies. This agrees well with the experiments, where SB-3CT is a more effective inhibitor of MMP2 than its sulfoxide analogue.

Project description:SB-3CT, (4-phenoxyphenylsulfonyl)methylthiirane, is a potent, mechanism-based inhibitor of the gelatinase sub-class of the matrix metalloproteinase (MMP) family of zinc proteases. The gelatinase MMPs are unusual in that there are several examples where both enantiomers of a racemic inhibitor have comparable inhibitory abilities. SB-3CT is one such example. Here, the inhibition mechanism of the MMP2 gelatinase by the (S)-SB-3CT enantiomer and its oxirane analogue is examined computationally, and compared to the mechanism of (R)-SB-3CT. Inhibition of MMP2 by (R)-SB-3CT was shown previously to involve enzyme-catalyzed C-H deprotonation adjacent to the sulfone, with concomitant opening by ?-elimination of the sulfur of the three-membered thiirane ring. Similarly to the R enantiomer, (S)-SB-3CT was docked into the active site of MMP2, followed by molecular dynamics simulation to prepare the complex for combined quantum mechanics and molecular mechanics (QM/MM) calculations. QM/MM calculations with B3LYP/6-311+G(d,p) for the QM part (46 atoms) and the AMBER force field for the MM part were used to compare the reaction of (S)-SB-3CT and its oxirane analogue in the active site of MMP2 (9208 atoms). These calculations show that the barrier for the proton abstraction coupled ring opening reaction of (S)-SB-3CT in the MMP2 active site is 4.4 kcal/mol lower than its oxirane analogue, and the ring opening reaction energy of (S)-SB-3CT is only 1.6 kcal/mol less exothermic than its oxirane analogue. Calculations also show that the protonation of the ring-opened products by water is thermodynamically much more favorable for the alkoxide obtained from the oxirane, than for the thiolate obtained from the thiirane. In contrast to (R)-SB-3CT and the R-oxirane analogue, the double bonds of the ring-opened products of (S)-SB-3CT and its S-oxirane analogue have the cis-configuration. Vibrational frequency and intrinsic reaction path calculations on a reduced size QM/MM model (2747 atoms) provide additional insight into the mechanism. These calculations yield 5.9 and 6.7 for the deuterium kinetic isotope effect for C-H bond cleavage in the transition state for the R and S enantiomers of SB-3CT, in good agreement with the experimental results.

Project description:Matrix metalloproteinases (MMPs) are the major proteolytic enzymes which assist in regulating the metastatic process by degrading the extracellular matrix proteins. In this study, we have investigated the anti-metastatic potential of major bioactive compounds in the medicinal plant Indigofera aspalathoides targeting matrix metalloproteinases (MMP2 & MMP9) and it's in silico pharmacokinetic profiles using computational studies. Indigofera aspalathoides (Sivanar vembu in Tamil) is a renowned medicinal herb in traditional Indian medicine which contains indigocarpan, mucronulatol, indigocarpan diacetate, erythroxydiol X and erythroxydiol Y as the major constituents. The 3-dimensional structure of MMP2 and MMP9 was designed by using I-tasser and Modeller and it was validated by PROCHECK. The structures of mucronulatol and indigocarpan have been retrieved from PubChem and indigocarpan diacetate, erythroxydiol X & Y were drawn by using Chemdraw Ultra 6.0. Batimastat was used as a positive control. Molecular docking was performed by using AutoDock 4.2 tools and AutoDock vina, an open-source program which signifies an effective interaction between the phytoligands and MMP2 & MMP9. From the results, AutoDock 4.2 have showed that indigocarpan possesses strong binding energy (ΔG) of - 7.68 kcal/mol towards MMP2 and - 6.35 kcal/mol towards MMP9, whereas batimastat showed binding energy (ΔG) of - 6.34 kcal/mol for MMP2 and - 5.66 kcal/mol for MMP9, meanwhile the results from AutoDock vina indicates that indigocarpan possesses strong binding energy (ΔG) of - 8.0 kcal/mol towards MMP2 and - 8.2 kcal/mol towards MMP9, whereas batimastat showed binding energy (ΔG) of - 7.2 kcal/mol for MMP2 and - 7.6 kcal/mol for MMP9. Also, the ADME and toxicity results suggest that the indigocarpan compound possesses a druggable pharmacokinetic potentiality and does not have carcinogenicity and Ames mutagenesis compared with other phytoligands. Hence, it is evident from our results that both AutoDock platforms strongly revealed that the phytoligand, indigocarpan possesses strong inhibitory activity against MMP2 and MMP9 to control cancer metastasis.Supplementary informationThe online version contains supplementary material available at 10.1007/s13205-021-02731-w.

Dataset Information

DFT studies of the ring-opening mechanism of SB-3CT, a potent inhibitor of matrix metalloproteinase 2.

Publications

DFT studies of the ring-opening mechanism of SB-3CT, a potent inhibitor of matrix metalloproteinase 2.

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