Sepehri Bakhtyar, Ghavami Raouf
Department of Chemistry, Faculty of Science, University of Kurdistan, Sanandaj, Iran.
Med Chem. 2018;14(5):439-450. doi: 10.2174/1573406414666180321151029.
HSP90 is necessary for the conformational maturation of proteins, proteins disaggregation, folding newly synthesized peptides and the refolding of denatured proteins. The inhibition of HSP90 leads to proteasomal degradations of client proteins that finally kill cancer cells.
In this research, molecular docking and comparative molecular field analysis (CoMFA) were used to investigate the interactions of tetrahydropyrido[4,3-d]pyrimidine derivatives with the N-terminal domain binding site of the HSP90 and predicting their inhibitory activities.
A CoMFA model with five components and q2 of 0.81 was developed. R2 for training and test sets were 0.96 and 0.79, respectively. Based on extracted Contour maps for this CoMFA model, three new inhibitors with greater pIC50 with respect to the greatest active molecule in the data-set were designed by modifying molecule m45. Molecule m45 and designed inhibitors were docked to the N-terminal domain binding site of the HSP90. Designed inhibitors obtained lower binding energy with respect to m45.
Based on extracted CoMFA contour maps, bulky substituents are favored for the R1 group and in R3 group, short and bulky substituents increase the activity of molecules. Less bulky and longer substituents are favored for R2. The molecular docking analysis of compound m45 with the N-terminal domain binding site of the HSP90 show hydroxyl group on phenyl ring is necessary to form hydrogen bonding with hydrophilic residues in binding site and a conserved water molecule. Molecule m45 has Pi-Sigma interaction with phenyl ring in the side chain of Phenylalanine 138 via isopropyl substituent on meta position of the phenyl ring. Also, Molecule m45 forms carbon-hydrogen bond with oxygen atoms at the side chain of Aspartic acid 54 and Asparagine 51 via its dimethylamine group. Others are Van der Waals interactions.
热休克蛋白90（HSP90）对于蛋白质的构象成熟、蛋白质解聚、新合成肽段的折叠以及变性蛋白质的复性是必需的。抑制HSP90会导致客户蛋白的蛋白酶体降解，最终杀死癌细胞。
在本研究中，采用分子对接和比较分子力场分析（CoMFA）来研究四氢吡啶并[4,3-d]嘧啶衍生物与HSP90 N端结构域结合位点的相互作用，并预测其抑制活性。
建立了一个包含五个成分且交叉验证系数q2为0.81的CoMFA模型。训练集和测试集的R2分别为0.96和0.79。基于该CoMFA模型提取的等高线图，通过修饰分子m45设计了三种相对于数据集中活性最强的分子具有更高pIC50的新型抑制剂。将分子m45和设计的抑制剂对接至HSP90的N端结构域结合位点。与m45相比，设计的抑制剂具有更低的结合能。
基于提取的CoMFA等高线图，R1基团倾向于大体积取代基，R3基团中短而大体积的取代基会增加分子的活性。R2基团倾向于体积较小且较长的取代基。化合物m45与HSP90 N端结构域结合位点的分子对接分析表明，苯环上的羟基对于与结合位点中的亲水性残基和一个保守水分子形成氢键是必需的。分子m45通过苯环间位的异丙基取代基与苯丙氨酸138侧链中的苯环形成π-σ相互作用。此外，分子m45通过其二甲胺基团与天冬氨酸54和天冬酰胺51侧链中的氧原子形成碳氢键。其他相互作用为范德华相互作用。
