Multiscale calculations reveal new insights into the reaction mechanism between KRASG12C and α, β-unsaturated carbonyl of covalent inhibitors
Utilizing α,β-unsaturated carbonyl group as Michael acceptors to react with thiols represents a successful strategy for developing KRASG12C inhibitors. Despite this, the precise reaction mechanism between KRASG12C and covalent inhibitors remains a subject of debate, primarily due to the absence of a...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-12-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037024000813 |
| _version_ | 1797215944841363456 |
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| author | Xiao Yan Chuanhua Qu Qin Li Lei Zhu Henry H.Y. Tong Huanxiang Liu Qin Ouyang Xiaojun Yao |
| author_facet | Xiao Yan Chuanhua Qu Qin Li Lei Zhu Henry H.Y. Tong Huanxiang Liu Qin Ouyang Xiaojun Yao |
| author_sort | Xiao Yan |
| collection | DOAJ |
| description | Utilizing α,β-unsaturated carbonyl group as Michael acceptors to react with thiols represents a successful strategy for developing KRASG12C inhibitors. Despite this, the precise reaction mechanism between KRASG12C and covalent inhibitors remains a subject of debate, primarily due to the absence of an appropriate residue capable of deprotonating the cysteine thiol as a base. To uncover this reaction mechanism, we first discussed the chemical reaction mechanism in solvent conditions via density functional theory (DFT) calculation. Based on this, we then proposed and validated the enzymatic reaction mechanism by employing quantum mechanics/molecular mechanics (QM/MM) calculation. Our QM/MM analysis suggests that, in biological conditions, proton transfer and nucleophilic addition may proceed through a concerted process to form an enolate intermediate, bypassing the need for a base catalyst. This proposed mechanism differs from previous findings. Following the formation of the enolate intermediate, solvent-assisted tautomerization results in the final product. Our calculations indicate that solvent-assisted tautomerization is the rate-limiting step in the catalytic cycle under biological conditions. On the basis of this reaction mechanism, the calculated kinact/ki for two inhibitors is consistent well with the experimental results. Our findings provide new insights into the reaction mechanism between the cysteine of KRASG12C and the covalent inhibitors and may provide valuable information for designing effective covalent inhibitors targeting KRASG12C and other similar targets. |
| first_indexed | 2024-04-24T11:38:07Z |
| format | Article |
| id | doaj.art-37ebd4bb93a74816a7cf0dcc4082dd13 |
| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-04-24T11:38:07Z |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-37ebd4bb93a74816a7cf0dcc4082dd132024-04-10T04:28:52ZengElsevierComputational and Structural Biotechnology Journal2001-03702024-12-012314081417Multiscale calculations reveal new insights into the reaction mechanism between KRASG12C and α, β-unsaturated carbonyl of covalent inhibitorsXiao Yan0Chuanhua Qu1Qin Li2Lei Zhu3Henry H.Y. Tong4Huanxiang Liu5Qin Ouyang6Xiaojun Yao7Faculty of Applied Sciences, Macao Polytechnic University, Macao Special Administrative Region of ChinaCollege of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing University of Arts and Sciences, Chongqing 402160, ChinaFaculty of Applied Sciences, Macao Polytechnic University, Macao Special Administrative Region of ChinaCollege of Pharmacy, Third Military Medical University, Shapingba, Chongqing 400038, ChinaFaculty of Applied Sciences, Macao Polytechnic University, Macao Special Administrative Region of ChinaFaculty of Applied Sciences, Macao Polytechnic University, Macao Special Administrative Region of China; Corresponding authors.College of Pharmacy, Third Military Medical University, Shapingba, Chongqing 400038, China; Corresponding authors.Faculty of Applied Sciences, Macao Polytechnic University, Macao Special Administrative Region of China; Corresponding authors.Utilizing α,β-unsaturated carbonyl group as Michael acceptors to react with thiols represents a successful strategy for developing KRASG12C inhibitors. Despite this, the precise reaction mechanism between KRASG12C and covalent inhibitors remains a subject of debate, primarily due to the absence of an appropriate residue capable of deprotonating the cysteine thiol as a base. To uncover this reaction mechanism, we first discussed the chemical reaction mechanism in solvent conditions via density functional theory (DFT) calculation. Based on this, we then proposed and validated the enzymatic reaction mechanism by employing quantum mechanics/molecular mechanics (QM/MM) calculation. Our QM/MM analysis suggests that, in biological conditions, proton transfer and nucleophilic addition may proceed through a concerted process to form an enolate intermediate, bypassing the need for a base catalyst. This proposed mechanism differs from previous findings. Following the formation of the enolate intermediate, solvent-assisted tautomerization results in the final product. Our calculations indicate that solvent-assisted tautomerization is the rate-limiting step in the catalytic cycle under biological conditions. On the basis of this reaction mechanism, the calculated kinact/ki for two inhibitors is consistent well with the experimental results. Our findings provide new insights into the reaction mechanism between the cysteine of KRASG12C and the covalent inhibitors and may provide valuable information for designing effective covalent inhibitors targeting KRASG12C and other similar targets.http://www.sciencedirect.com/science/article/pii/S2001037024000813KRASG12CCovalent InhibitorsQM/MMDFTReaction Mechanism |
| spellingShingle | Xiao Yan Chuanhua Qu Qin Li Lei Zhu Henry H.Y. Tong Huanxiang Liu Qin Ouyang Xiaojun Yao Multiscale calculations reveal new insights into the reaction mechanism between KRASG12C and α, β-unsaturated carbonyl of covalent inhibitors Computational and Structural Biotechnology Journal KRASG12C Covalent Inhibitors QM/MM DFT Reaction Mechanism |
| title | Multiscale calculations reveal new insights into the reaction mechanism between KRASG12C and α, β-unsaturated carbonyl of covalent inhibitors |
| title_full | Multiscale calculations reveal new insights into the reaction mechanism between KRASG12C and α, β-unsaturated carbonyl of covalent inhibitors |
| title_fullStr | Multiscale calculations reveal new insights into the reaction mechanism between KRASG12C and α, β-unsaturated carbonyl of covalent inhibitors |
| title_full_unstemmed | Multiscale calculations reveal new insights into the reaction mechanism between KRASG12C and α, β-unsaturated carbonyl of covalent inhibitors |
| title_short | Multiscale calculations reveal new insights into the reaction mechanism between KRASG12C and α, β-unsaturated carbonyl of covalent inhibitors |
| title_sort | multiscale calculations reveal new insights into the reaction mechanism between krasg12c and α β unsaturated carbonyl of covalent inhibitors |
| topic | KRASG12C Covalent Inhibitors QM/MM DFT Reaction Mechanism |
| url | http://www.sciencedirect.com/science/article/pii/S2001037024000813 |
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