In silico design of novel anticancer drugs with amino acid and carbohydrate building blocks to inhibit PIM kinases

PIM-1 is a serine-threonine kinase mainly expressed in tissues like the Thymus, spleen, bone marrow, and liver. Overexpression of PIM kinases occurs in various types of human tumours, such as lymphomas, prostate cancer, and oral cancer. As a result, the design of drugs to inhibit PIM-1 in cancerous cells has attracted much attention in recent years. This study aimed to design the alternative inhibitors for PIM-1 kinase, which are based on carbohydrates and amino acids and are expected to be non-toxic with the same chemotherapeutic effects as the traditional known anticancer drugs. The combinatorial use of quantum mechanics (QM) and molecular dynamic simulation (MD) has enabled us to precisely predict the inhibition of PIM-1 kinase by the novel designed drugs and compare them with the recently synthesized chemotherapeutic drugs such as DBC (Table 1). All designed structures were optimized at the B3LYP/6-311++G(d,p) level. The designed structure UNK4 (Table 1) was the most similar structure to DBC in terms of volumes, areas, and electrostatic potential map to DBC. The results obtained in this research represented that UNK4, with the building blocks of amino acid and cyclic carbohydrates could be considered an alternative anticancer drug for DBC.

PIM-1是一种丝氨酸-苏氨酸激酶（serine-threonine kinase），主要在胸腺、脾脏、骨髓与肝脏等组织中表达。PIM激酶的过表达可见于多种人类肿瘤，例如淋巴瘤、前列腺癌及口腔癌。因此，近年来开发靶向癌细胞内PIM-1的抑制药物受到了广泛关注。本研究旨在开发基于糖类与氨基酸的PIM-1激酶新型替代抑制剂，以期获得与传统已知抗癌药物疗效相当且无毒副作用的候选化合物。本研究组合运用量子力学（quantum mechanics，QM）与分子动力学模拟（molecular dynamic simulation，MD），能够精准预测新型设计药物对PIM-1激酶的抑制活性，并将其与近期合成的DBC等化疗药物进行对比（详见表1）。所有设计得到的分子结构均在B3LYP/6-311++G(d,p)水平下完成几何优化。设计得到的结构UNK4（见表1）在分子体积、表面积与静电势能图谱方面与DBC最为相似。本研究结果表明，以氨基酸与环状糖类为结构单元的UNK4可作为DBC的替代抗癌候选药物。