One of the most prevalent cancers in men is prostate cancer and could be managed with immunotoxins or antibody treatment. Because of the substantial rise of the Prostate-Specific Antigen and the Prostate-Specific Membrane Antigen (PSMA), cancer vaccination should be rendered with these antigens. Through pharmacodynamic experiments in a library of natural compounds from ZINC database, the current research sought to identify compounds that could suppress PSMA protein. To test the most productive compounds for further research, the Library has been scanned with Pharmacophore and ADMET analysis followed by molecular docking methods in the first phase. After selecting 15 ligands with the best pose related to docking results, to evaluate the stability of the ligand-protein bounds of the compounds, a molecular dynamics simulation considering the effect of the presence of zinc ions on the protein structure was performed. The measurement of ligand binding modes and free energy has shown that four compounds, including Z10, Z06, Z01, and Z03, have formed critical interactions with the active site's residues. Besides, multiple approaches were employed to determine their inhibition rating and describe the variables that facilitate the attachment of ligands to the protein active site. The results are obtained from the MMPBSA/GBSA analysis of four selected small molecules (Z10, Z06, Z01, and Z03), which are very close to the IC50 value of reference ligand (DCIBzl); they are −13.85 kcal/mol, −12.58 kcal/mol, −10.71 kcal/mol and −9.39 kcal/mol respectively. Finally, we evaluate the results obtained from selected ligands using hydrogen bond and decomposition analyzes. We have examined the effective interactions between ligands and S1/S1ˊpockets in protein. Our computational results illustrate the design of more efficient inhibitors of PSMA.

男性中最普遍的癌症之一是前列腺癌，可以通过免疫毒素或抗体治疗来控制。由于前列腺特异性抗原和前列腺特异性膜抗原（PSMA）的大量增加，应使用这些抗原进行癌症疫苗接种。通过在ZINC数据库中的天然化合物库中进行药效实验，当前的研究试图确定可抑制PSMA蛋白的化合物。为了测试最具生产力的化合物以供进一步研究，已在第一阶段使用Pharmacophore和ADMET分析扫描了该文库，然后进行了分子对接方法。在选择15个与对接结果相关的姿态最佳的配体后，要评估化合物的配体-蛋白质结合的稳定性，进行了考虑锌离子存在对蛋白质结构影响的分子动力学模拟。配体结合模式和自由能的测量表明，包括Z10，Z06，Z01和Z03在内的四种化合物已与活性位点的残基形成了关键的相互作用。此外，采用了多种方法来确定其抑制率，并描述了促进配体与蛋白质活性位点结合的变量。结果是通过对四个选定的小分子（Z10，Z06，Z01和Z03）的MMPBSA / GBSA分析获得的，它们非常接近参考配体（DCIBzl）的IC50值；它们分别是-13.85kcal / mol，-12.88kcal / mol，-10.71kcal / mol和-9.39kcal / mol。最后，我们使用氢键和分解分析评估从选定的配体获得的结果。我们已经检查了配体和蛋白质中的S1 / S1ˊ口袋之间的有效相互作用。我们的计算结果说明了更有效的PSMA抑制剂的设计。