Elsaman Tilal, Awadalla Mohamed Khalid Alhaj, Mohamed Malik Suliman, Eltayib Eyman Mohamed, Mohamed Magdi Awadalla
Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72388, Saudi Arabia.
Pharmacy Program, Wad Medani College of Medical Sciences and Technology, Wad Medani 21111, Gezira, Sudan.
Pharmaceuticals (Basel). 2025 Apr 20;18(4):598. doi: 10.3390/ph18040598.
Eumycetoma, caused by , is a chronic fungal infection with limited treatment options and increasing drug resistance. CYP51, a key enzyme in ergosterol biosynthesis, is a well-established target for azole antifungals. However, existing azole drugs demonstrate limited efficacy in treating eumycetoma. Microbial-based natural products, with their structural diversity and bioactivity, offer a promising source for novel CYP51 inhibitors. This study aimed to identify potential CYP51 inhibitors from microbial natural products using molecular docking, MM-GBSA calculations, ADMET analysis, and molecular dynamics (MD) simulations. Virtual screening was conducted on a library of microbial-based natural products using an in-house homology model of CYP51, with itraconazole as the reference drug. The top compounds from initial docking were refined through Standard and Extra Precision docking. MM-GBSA calculations assessed binding affinities, and ADMET analysis evaluated drug-like properties. Compounds with favorable properties underwent MD simulations. The computational investigations identified 34 compounds with better docking scores and binding affinity than itraconazole. Of these, 9 compounds interacted with the heme group and key residues in the active site of CYP51. In silico pharmacokinetic profiling identified 3 compounds as promising candidates, and MD simulations confirmed their potential as CYP51 inhibitors. The study highlights microbial-derived natural products, particularly monacyclinone G, H, and I, as promising candidates for CYP51 inhibition, with the potential for treating eumycetoma, requiring further experimental validation.
足菌肿是由……引起的一种慢性真菌感染，治疗选择有限且耐药性不断增加。CYP51是麦角甾醇生物合成中的关键酶，是已确立的唑类抗真菌药物的作用靶点。然而，现有的唑类药物在治疗足菌肿方面疗效有限。基于微生物的天然产物具有结构多样性和生物活性，为新型CYP51抑制剂提供了一个有前景的来源。本研究旨在通过分子对接、MM-GBSA计算、ADMET分析和分子动力学（MD）模拟，从微生物天然产物中鉴定潜在的CYP51抑制剂。使用CYP51的内部同源模型，以伊曲康唑为参考药物，对基于微生物的天然产物库进行虚拟筛选。初始对接得到的顶级化合物通过标准对接和高精度对接进行优化。MM-GBSA计算评估结合亲和力，ADMET分析评估类药性质。具有良好性质的化合物进行MD模拟。计算研究确定了34种对接分数和结合亲和力优于伊曲康唑的化合物。其中，9种化合物与CYP51活性位点的血红素基团和关键残基相互作用。计算机模拟的药代动力学分析确定了3种化合物为有前景的候选物，MD模拟证实了它们作为CYP51抑制剂的潜力。该研究强调了微生物来源的天然产物，特别是单环菌素G、H和I，作为CYP51抑制的有前景的候选物，具有治疗足菌肿的潜力，需要进一步的实验验证。
