The CBP (CREB-binding protein) and p300 are related to transcriptional coactivator family and are involved in several post-translational modifications, in which the acetylation is an important factor because it commences the transcription process. Experimental studies report that CTPB (N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide) and CTB (N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxybenzamide) are good activators of p300 HAT enzyme, but yet, the molecular mechanism of their activation is not explored. The present study pertains to determine the intermolecular interactions, stability and binding free energy of CTB and CTPB from the molecular docking, molecular dynamics (MD) simulation and binding free energy calculation. The docking studies of the molecules reveal that the docking score of CTPB (−15.64 kcal/mol) is higher than that of CTB (−12.30 kcal/mol); on the contrary, CTB forms a strong interaction with the key residues of catalytic site (Tyr1467 and Trp1436) compared with CTPB. The MD simulation shows the stability of both molecules in the active site of p300 and their interactions. Furthermore, both docking and MD simulation studies of CTB confirm that it forms expected key interactions and retain the interactions with the active site amino acid residues of p300 when compared with CTPB. For this reason, the CTB recruits more acetyl-CoA in the active site of p300 compared with CTPB; it leads to activate the acetylation process; hence, CTB may be a best activator than CTPB. The binding free energy value of CTPB (−24.79 $\pm$ 2.38 kcal/mol) is higher when compared with that of CTB (−12.14 $\pm$ 1.30 kcal/mol) molecule; perhaps, the interaction of pentadecyl chain of CTPB with p300, whereas in CTB, such a group is absent.

Communicated by Ramaswamy H. Sarma

CBP（CREB结合蛋白）和p300与转录共激活因子家族有关，并参与几种翻译后修饰，其中乙酰化是一个重要因素，因为它开始了转录过程。实验研究报告CTPB（N-（4-氯-3-三氟甲基-苯基）-2-乙氧基-6-十五烷基-苯甲酰胺）和CTB（N-（4-氯-3-三氟甲基-苯基）-2-乙氧基苯甲酰胺）是p300 HAT酶的良好活化剂，但尚未探讨其活化的分子机理。本研究涉及通过分子对接，分子动力学（MD）模拟和结合自由能计算确定CTB和CTPB的分子间相互作用，稳定性和结合自由能。分子的对接研究表明，CTPB的对接得分（−15.64 kcal / mol）高于CTB的对接得分（−12.30 kcal / mol）。相反，与CTPB相比，CTB与催化位点的关键残基（Tyr1467和Trp1436）形成强烈的相互作用。MD模拟显示了两个分子在p300活性位点的稳定性及其相互作用。此外，CTB的对接和MD模拟研究均证实，与CTPB相比，它形成了预期的关键相互作用并保留了与p300活性位点氨基酸残基的相互作用。因此，与CTPB相比，CTB在p300的活性位点吸收了更多的乙酰辅酶A。它导致激活乙酰化过程；因此，CTB可能是比CTPB最好的活化剂。CTPB的结合自由能值（−24.79 $\pm$ 与CTB相比更高（2.38 kcal / mol）（−12.14 $\pm$ 1.30 kcal / mol）分子；可能是CTPB的十五烷基链与p300相互作用，而在CTB中则没有这样的基团。

由Ramaswamy H.Sarma沟通