Covalent inhibition targeting noncatalytic residues is rapidly gaining attention in drug discovery. Protein tyrosine phosphatases 1B (PTP1B) is an attractive target for therapeutic interventions in cancer and other diseases. Two binding sites of PTP1B enzyme were identified, catalytic and allosteric. The catalytic site is deep and narrow which protects the active site amino acid residue Cys215 from covalent inhibition, whereas the allosteric site is more hydrophobic and less conserved with Cys121 residue, to which covalent inhibitors can bind. A recent experimental report highlighted that a highly selective inhibitor, 73U, was found to bind covalently in the allosteric region of PTP1B enzyme. Using a robust covalent simulations protocol which was developed in-house, we explore the origin and impact of covalent inhibition upon inhibitor binding to allosteric site. For this, covalently bound and apo enzymes were investigated. Results revealed that allosteric covalent inhibition has ensued in a significant disturbance in the overall network of interaction between Cys121 and other nearby residues, more specifically Tyr124 and His214. The covalent inhibition also exhibited better protein stability as evident from positive correlation between residues in the allosteric site and multiple van der Waal, hydrogen bond and ionic interactions. Surface analysis revealed an increase in the accessible surface area in order to facilitate for the covalent inhibitor to sink in. These findings indicate that exploring allosteric covalent mechanism of PTP1B enzyme offers an opportunity to develop novel PTP1B covalent inhibitors with high potency and selectivity for cancer and other diseases.

中文翻译：

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“变构Cys121”的选择性共价抑制扭曲了PTP1B酶的结合：一种新型的癌症治疗方法。

针对非催化残基的共价抑制在药物发现中迅速引起关注。蛋白质酪氨酸磷酸酶1B（PTP1B）是癌症和其他疾病的治疗性干预措施的一个有吸引力的目标。确定了PTP1B酶的两个结合位点，催化位点和变构位点。催化位点较深且较窄，可保护活性位点氨基酸残基Cys215免受共价抑制，而变构位点则疏水性更高，与共价抑制剂可结合的Cys121残基保守性较低。最近的一项实验报告强调，发现高选择性抑制剂73U与PTP1B酶的变构区共价结合。使用内部开发的强大的共价模拟协议，我们探索了共价抑制作用对抑制剂结合变构位点的起源和影响。为此，研究了共价结合酶和载脂蛋白酶。结果显示，变构共价抑制已导致Cys121与其他附近残基（更具体地说是Tyr124和His214）之间的相互作用的整体网络受到重大干扰。共价抑制也表现出更好的蛋白质稳定性，这从变构位点中的残基与多个范德华力，氢键和离子相互作用之间呈正相关可明显看出。表面分析显示可及表面积增加，以促进共价抑制剂沉入。