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论文题目: The in silico identification of small molecules for protein-protein interaction inhibition in AKAP-Lbc-RhoA signaling complex
英文论文题目: The in silico identification of small molecules for protein-protein interaction inhibition in AKAP-Lbc-RhoA signaling complex
第一作者: Khan, A; Munir, M; Aiman, S; Wadood, A; Khan, AU
英文第一作者: Khan, A; Munir, M; Aiman, S; Wadood, A; Khan, AU
联系作者: Khan, A (reprint author), Abdul Wali Khan Univ Mardan, Dept Biochem, Mardan 23200, Pakistan.
英文联系作者: Khan, A (reprint author), Abdul Wali Khan Univ Mardan, Dept Biochem, Mardan 23200, Pakistan.
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发表年度: 2017
卷: 67
期:
页码: 84-91
摘要: The rational design of small molecules that mimic key residues at the interface of interacting proteins can be a successful approach to target certain biological signaling cascades causing pathophysiological outcome. The A-Kinase Anchoring Protein, i.e. AKAP-Lbc, catalyses nucleotide exchange on RhoA and is involved in cardiac repolarization. The oncogenic AKAP-Lbc induces the RhoA GTPase hyperactivity and aberrantly amplifies the signaling pathway leading to hypertrophic cardiomyocytes. We took advantage of the AKAP-Lbc-RhoA complex crystal structure to design in silico small molecules predicted to inhibit the associated pathological signaling cascade. We adopted the strategies of pharmacophore building, virtual screening and molecular docking to identify the small molecules capable to target AKAP-Lbc and RhoA interactions. The pharmacophore model based virtual screening unveils two lead compounds from the TIMBAL database of small molecules modulating the targeted protein-protein interactions. The molecular docking analysis revealed the lead compounds ' potentialities to establish the essential chemical interactions with the key interactive residues of the complex. These features provided a road map for designing additional potent chemical derivatives and fragments of the original lead compounds to perturb the AKAP-Lbc and RhoA interactions. Experimental validations may elucidate the therapeutic potential of these lead chemical scaffolds to deal with aberrant AKAP-Lbc signaling based cardiac hypertrophy.
英文摘要: The rational design of small molecules that mimic key residues at the interface of interacting proteins can be a successful approach to target certain biological signaling cascades causing pathophysiological outcome. The A-Kinase Anchoring Protein, i.e. AKAP-Lbc, catalyses nucleotide exchange on RhoA and is involved in cardiac repolarization. The oncogenic AKAP-Lbc induces the RhoA GTPase hyperactivity and aberrantly amplifies the signaling pathway leading to hypertrophic cardiomyocytes. We took advantage of the AKAP-Lbc-RhoA complex crystal structure to design in silico small molecules predicted to inhibit the associated pathological signaling cascade. We adopted the strategies of pharmacophore building, virtual screening and molecular docking to identify the small molecules capable to target AKAP-Lbc and RhoA interactions. The pharmacophore model based virtual screening unveils two lead compounds from the TIMBAL database of small molecules modulating the targeted protein-protein interactions. The molecular docking analysis revealed the lead compounds ' potentialities to establish the essential chemical interactions with the key interactive residues of the complex. These features provided a road map for designing additional potent chemical derivatives and fragments of the original lead compounds to perturb the AKAP-Lbc and RhoA interactions. Experimental validations may elucidate the therapeutic potential of these lead chemical scaffolds to deal with aberrant AKAP-Lbc signaling based cardiac hypertrophy.
刊物名称: COMPUTATIONAL BIOLOGY AND CHEMISTRY
英文刊物名称: COMPUTATIONAL BIOLOGY AND CHEMISTRY
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学科: Biology; Computer Science, Interdisciplinary Applications
英文学科: Biology; Computer Science, Interdisciplinary Applications
影响因子: 1.331
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论文类别: Article
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