Sama-Ae Imran, Pattaranggoon Nawanwat C, Tedasen Aman
School of Allied Health Sciences, Walailak University, 80161, Nakhon Si Thammarat, Thailand.
Program in Bioinformatics and Computational Biology, Chulalongkorn University, 10330, Bangkok, Thailand.
J Mol Graph Model. 2023 Jun;121:108435. doi: 10.1016/j.jmgm.2023.108435. Epub 2023 Feb 16.
An increase in the occurrence of fungal infections throughout the world, as well as the rise of novel fungal strains and antifungal resistance to commercially available drugs, suggests that new therapeutic choices for fungal infections are needed. The purpose of this research was to find new antifungal candidates or leads of secondary metabolites derived from natural sources that could effectively inhibit the enzymatic activity of Candida albicans lanosterol 14-alpha demethylase (CYP51) while also having good pharmacokinetics. In silico prediction of the drug-likeness, chemo-informatics and enzyme inhibition indicate that the 46 compounds derived from fungi, sponges, plants, bacteria and algae sources have a high novelty to meet all five requirements of Lipinski's rules and impede enzymatic function. Among the 15 candidate molecules with strong binding affinity to CYP51 investigated by molecular docking simulation, didymellamide A-E compounds demonstrated the strongest binding energy against the target protein at -11.14, -11.46, -11.98, -11.98, and -11.50 kcal/mol, respectively. Didymellamide molecules bind to comparable active pocket sites of antifungal ketoconazole and itraconazole medicines by hydrogen bonds forming to Tyr132, Ser378, Met508, His377 and Ser507, and hydrophobic interactions with HEM601 molecule. The stability of the CYP51-ligand complexes was further investigated using molecular dynamics simulations that took into account different geometric features and computed binding free energy. Using the pkCSM ADMET descriptors tool, several pharmacokinetic characteristics and the toxicity of candidate compounds were assessed. The findings of this study revealed that didymellamides could be a promising inhibitor against these CYP51 protein. However, there is still a need for further in vivo and in vitro studies to support these findings.
全球真菌感染发生率的增加，以及新型真菌菌株的出现和对市售药物的抗真菌耐药性，表明需要新的真菌感染治疗选择。本研究的目的是寻找新的抗真菌候选物或源自天然来源的次生代谢产物先导物，这些先导物可以有效抑制白色念珠菌羊毛甾醇14-α脱甲基酶（CYP51）的酶活性，同时还具有良好的药代动力学。药物相似性、化学信息学和酶抑制的计算机模拟预测表明，源自真菌、海绵、植物、细菌和藻类来源的46种化合物具有很高的新颖性，能够满足Lipinski规则的所有五项要求并阻碍酶功能。在通过分子对接模拟研究的与CYP51具有强结合亲和力的15种候选分子中，双隔孢酰胺A-E化合物对靶蛋白的结合能最强，分别为-11.14、-11.46、-11.98、-11.98和-11.50千卡/摩尔。双隔孢酰胺分子通过与Tyr132、Ser378、Met508、His377和Ser507形成氢键以及与HEM601分子的疏水相互作用，与抗真菌酮康唑和伊曲康唑药物的类似活性口袋位点结合。使用考虑了不同几何特征并计算结合自由能的分子动力学模拟，进一步研究了CYP51-配体复合物的稳定性。使用pkCSM ADMET描述符工具，评估了候选化合物的几种药代动力学特征和毒性。本研究结果表明，双隔孢酰胺可能是一种有前途的CYP51蛋白抑制剂。然而，仍需要进一步的体内和体外研究来支持这些发现。
