Sakyi Patrick O, Kwofie Samuel K, Tuekpe Julius K, Gwira Theresa M, Broni Emmanuel, Miller Whelton A, Wilson Michael D, Amewu Richard K
Department of Chemistry, School of Physical and Mathematical Sciences, College of Basic and Applied Sciences, University of Ghana, Legon, Accra P.O. Box LG 56, Ghana.
Department of Chemical Sciences, School of Sciences, University of Energy and Natural Resources, Sunyani P.O. Box 214, Ghana.
Pharmaceuticals (Basel). 2023 Feb 21;16(3):330. doi: 10.3390/ph16030330.
The recent outlook of leishmaniasis as a global public health concern coupled with the reportage of resistance and lack of efficacy of most antileishmanial drugs calls for a concerted effort to find new leads. The study combined and in vitro approaches to identify novel potential synthetic small-molecule inhibitors targeting the sterol methyltransferase (SMT). The SMT enzyme in the ergosterol biosynthetic pathway is required for the parasite's membrane fluidity, distribution of membrane proteins, and control of the cell cycle. The lack of SMT homologue in the human host and its conserved nature among all parasites makes it a viable target for future antileishmanial drugs. Initially, six known inhibitors of SMT with IC < 10 μM were used to generate a pharmacophore model with a score of 0.9144 using LigandScout. The validated model was used to screen a synthetic library of 95,630 compounds obtained from InterBioScreen limited. Twenty compounds with pharmacophore fit scores above 50 were docked against the modelled three-dimensional structure of SMT using AutoDock Vina. Consequently, nine compounds with binding energies ranging from -7.5 to -8.7 kcal/mol were identified as potential hit molecules. Three compounds comprising STOCK6S-06707, STOCK6S-84928, and STOCK6S-65920 with respective binding energies of -8.7, -8.2, and -8.0 kcal/mol, lower than 22,26-azasterol (-7.6 kcal/mol), a known SMT inhibitor, were selected as plausible lead molecules. Molecular dynamics simulation studies and molecular mechanics Poisson-Boltzmann surface area calculations showed that the residues Asp25 and Trp208 were critical for ligand binding. The compounds were also predicted to have antileishmanial activity with reasonable pharmacological and toxicity profiles. When the antileishmanial activity of the three hits was evaluated in vitro against the promastigotes of , mean half-maximal inhibitory concentrations (IC) of 21.9 ± 1.5 μM (STOCK6S-06707), 23.5 ± 1.1 μM (STOCK6S-84928), and 118.3 ± 5.8 μM (STOCK6S-65920) were obtained. Furthermore, STOCK6S-84928 and STOCK6S-65920 inhibited the growth of , with IC of 14.3 ± 2.0 μM and 18.1 ± 1.4 μM, respectively. The identified compounds could be optimised to develop potent antileishmanial therapeutic agents.
利什曼病最近已成为全球公共卫生关注的焦点，再加上多数抗利什曼原虫药物出现耐药性报道且疗效不佳，这就需要共同努力寻找新的线索。该研究结合了体内和体外方法，以鉴定针对甾醇甲基转移酶（SMT）的新型潜在合成小分子抑制剂。麦角固醇生物合成途径中的SMT酶对于寄生虫的膜流动性、膜蛋白分布以及细胞周期控制是必需的。人类宿主中缺乏SMT同源物，且其在所有利什曼原虫中具有保守性，这使其成为未来抗利什曼病药物的可行靶点。最初，使用六种已知的IC<10μM的SMT抑制剂，通过LigandScout生成了一个得分0.9144的药效团模型。经过验证的模型用于筛选从InterBioScreen有限公司获得的95,630种化合物的合成文库。使用AutoDock Vina将20种药效团拟合得分高于50的化合物与SMT的三维模型结构对接。结果，鉴定出九种结合能范围为-7.5至-8.7 kcal/mol的化合物作为潜在的命中分子。三种化合物STOCK6S-06707、STOCK6S-84928和STOCK6S-65920，其各自的结合能分别为-8.7、-8.2和-8.0 kcal/mol，低于已知的SMT抑制剂22,26-氮杂甾醇（-7.6 kcal/mol），被选为合理的先导分子。分子动力学模拟研究和分子力学泊松-玻尔兹曼表面积计算表明，Asp25和Trp208残基对于配体结合至关重要。这些化合物还被预测具有合理的药理和毒性特征的抗利什曼原虫活性。当在体外评估这三种命中化合物对杜氏利什曼原虫前鞭毛体的抗利什曼原虫活性时，得到的平均半数最大抑制浓度（IC）分别为21.9±1.5μM（STOCK6S-06707）、23.5±1.1μM（STOCK6S-84928）和118.3±5.8μM（STOCK6S-65920）。此外，STOCK6S-84928和STOCK6S-65920抑制了杜氏利什曼原虫的生长，IC分别为14.3±2.0μM和18.1±1.4μM。所鉴定的化合物可以进行优化，以开发有效的抗利什曼病治疗药物。
