Federico Leonardo Bruno, Silva Guilherme Martins, Gomes Suzane Quintana, Francischini Isaque Antonio Galindo, Barcelos Mariana Pegrucci, Dos Santos Cleydson Breno Rodrigues, Costa Luciano T, Campos Rosa Joaquín María, de Paula da Silva Carlos Henrique Tomich
Computational Laboratory of Pharmaceutical Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. Do Café, S/n, Ribeirão Preto, SP, 14040-903, Brazil.
Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, 14040-901, Ribeirão Preto, SP, Brazil.
Comput Biol Med. 2021 Oct;137:104817. doi: 10.1016/j.compbiomed.2021.104817. Epub 2021 Aug 28.
Microtubules have been widely studied in recent decades as an important pharmacological target for the treatment of cancer especially due to its key role in the mitosis process. Among the constituents of the microtubules, αβ-tubulin dimers stand out in view of their four distinct interaction sites, including the so-called colchicine binding site (CBS) - a promising target for the development of new tubulin modulators. When compared to other tubulin sites, targeting the CBS is advantageous because this site is able to host ligands with lower molecular volume and lipophilicity, thus reducing the chances of entailing the phenomenon of multiple drug resistance (MDR) - one of the main reasons of failure in chemotherapy. However, colchicine, the first ligand ever discovered with affinity towards the CBS, despite modulating the action of microtubules, has shown toxicity in clinical studies. Therefore, in order to expand the known chemical space of scaffolds capable of interacting with CBS and to design non-toxic colchicine binding site inhibitors, we conducted a robust virtual screening pipeline. This has been rigorously validated and consisted of ligand- and structure-based methodologies, which allowed us to select four promising CBS inhibitors called tubLCQF1-4. These four compounds were also evaluated with long trajectories molecular dynamics simulations and respective results were used for the theoretical determination of the free energy released in the formation of the complexes, using the Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) methodology.
近几十年来，微管作为癌症治疗的重要药理学靶点得到了广泛研究，特别是因为它在有丝分裂过程中起着关键作用。在微管的组成成分中，αβ-微管蛋白二聚体因其四个不同的相互作用位点而格外突出，其中包括所谓的秋水仙碱结合位点（CBS）——这是开发新型微管蛋白调节剂的一个有前景的靶点。与其他微管蛋白位点相比，靶向CBS具有优势，因为该位点能够容纳分子体积和脂溶性较低的配体，从而降低产生多药耐药性（MDR）现象的可能性——MDR是化疗失败的主要原因之一。然而，秋水仙碱是首个被发现对CBS具有亲和力的配体，尽管它能调节微管的作用，但在临床研究中已显示出毒性。因此，为了扩展能够与CBS相互作用的已知化学空间，并设计无毒的秋水仙碱结合位点抑制剂，我们开展了一个强大的虚拟筛选流程。该流程经过了严格验证，由基于配体和结构的方法组成，这使我们能够筛选出四种有前景的CBS抑制剂，即tubLCQF1-4。我们还使用长轨迹分子动力学模拟对这四种化合物进行了评估，并使用分子力学泊松-玻尔兹曼表面积（MM/PBSA）方法，将各自的结果用于理论测定复合物形成过程中释放的自由能。
