Almasabi Saleh Hussain A, Almasoudi Hassan H, Albargy Hassan, Alabbas Meshal Mansour A, Al-Mansour Fares Saeed H
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Najran University, 61441, Najran, Saudi Arabia.
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Shaqra University, Shaqra, Riyadh, Saudi Arabia.
Med Oncol. 2025 Mar 29;42(5):143. doi: 10.1007/s12032-025-02700-w.
Cervical cancer develops due to the uncontrolled growth of abnormal cells in the cervix, mainly triggered by a persistent infection with high-risk types of human papillomavirus (HPV), a sexually transmitted virus. Factors that increase the risk include having multiple sexual partners, engaging in sexual activity at an early age, smoking, and a compromised immune system. Globally, it ranks as the fourth most prevalent cancer among women, with over 600000 new cases and 340000 deaths each year. The disease disproportionately impacts women in low- and middle-income countries, where access to screening and vaccination is often limited. Drug resistance emerges when cancer cells evade treatment through genetic mutations, altered targets, and efflux pump overexpression. Multitargeted docking identifies compounds interacting with multiple targets where a drug can inhibit crucial pathways, improving efficacy and reducing resistance chances. In this study, we examined Transferase, Cell Cycle Signalling, and Transport Proteins associated with PDB IDs 2WVI, 2B9R, 3VHX, and 3KND. These targets were subjected to multitargeted docking using an FDA-approved drug library. Droxidopa was identified as a multitargeted drug, with docking scores ranging from - 5.99 to - 11.37 kcal/mol and MM/GBSA scores between - 20.13 and - 43.00 kcal/mol. The interaction fingerprints identified the most interacted residues with counts are 4GLN, 4GLU, 3ARG, and 3TRP, and the Pharmacokinetics and DFT analysis favoured the compound's suitability. Furthermore, 5 ns (nanoseconds) WaterMap for hydration sites and 100 ns MD simulation in NPT ensemble at 330 K temperature have resulted in acceptable deviations, fluctuations, and many intermolecular interactions, and binding free energy computations have favoured droxidopa's use against cervical cancer-however, experimental studies are needed before its use including the in-vitro and in-vivo studies.
宫颈癌是由于宫颈中异常细胞不受控制地生长而发展形成的，主要由持续性感染高危型人乳头瘤病毒（HPV）引发，HPV是一种性传播病毒。增加风险的因素包括有多个性伴侣、过早进行性行为、吸烟以及免疫系统受损。在全球范围内，宫颈癌是女性中第四大最常见的癌症，每年有超过60万新发病例和34万例死亡。该疾病对低收入和中等收入国家的女性影响尤为严重，在这些国家，筛查和疫苗接种的可及性往往有限。当癌细胞通过基因突变、靶点改变和外排泵过度表达逃避治疗时，就会出现耐药性。多靶点对接可识别与多个靶点相互作用的化合物，药物可通过抑制关键途径来提高疗效并降低产生耐药性的几率。在本研究中，我们研究了与蛋白质数据银行（PDB）ID为2WVI、2B9R、3VHX和3KND相关的转移酶、细胞周期信号传导蛋白和转运蛋白。使用美国食品药品监督管理局（FDA）批准的药物库对这些靶点进行多靶点对接。左旋多巴被确定为一种多靶点药物，对接分数在-5.99至-11.37千卡/摩尔之间，分子力学/广义玻恩表面面积（MM/GBSA）分数在-20.13至-43.00千卡/摩尔之间。相互作用指纹图谱确定了相互作用最多的残基，数量最多的是4GLN、4GLU、3ARG和3TRP，药代动力学和密度泛函理论（DFT）分析表明该化合物具有适用性。此外，在330K温度下对水化位点进行5纳秒的水图分析以及在NPT系综中进行100纳秒的分子动力学（MD）模拟，得到了可接受的偏差、波动以及许多分子间相互作用，结合自由能计算支持左旋多巴用于治疗宫颈癌——然而，在使用之前还需要进行实验研究，包括体外和体内研究。
