The impact of autophagy on cancer treatment and its corresponding responsiveness has galvanized the scientific community to develop novel inhibitors for cancer treatment. Importantly, the discovery of inhibitors that targets the early phase of autophagy was identified as a beneficial choice. Despite the number of research in recent years, screening of the DrugBank repository (9591 molecules) for the Vacuolar protein sorting 34 (VPS34) has not been reported earlier. Therefore, the present study was designed to identify potential VPS34 antagonists using integrated pharmacophore strategies. Primarily, an energy-based pharmacophore and receptor cavity-based analysis yielded five (DHRRR) and seven featured (AADDHRR) pharmacophore hypotheses respectively, which were utilized for the database screening process. The glide score, the binding free energy, pharmacokinetics and pharmacodynamics properties were examined to narrow down the screened compounds. This analysis yielded a hit molecule, DB03916 that exhibited a better docking score, higher binding affinity and better drug-like properties in contrast to the reference compound that suffers from a toxicity property. Importantly, the result was validated using a 50 ns molecular dynamics simulation study. Overall, we conclude that the identified hit molecule DB03916 is believed to serve as a prospective antagonist against VPS34 for cancer treatment.

自噬对癌症治疗及其相应反应性的影响激励了科学界开发新型的癌症治疗抑制剂。重要的是，发现靶向自噬早期的抑制剂被认为是有益的选择。尽管近年来进行了许多研究，但较早前尚未报道过筛选DrugBank信息库（9591分子）中的Vacuolar蛋白质分选34（VPS34）的信息。因此，本研究旨在使用整合的药效团策略鉴定潜在的VPS34拮抗剂。首先，基于能量的药效基团和基于受体腔的分析分别产生了五个（DHRRR）和七个特征（AADDHRR）药效基团假设，这些假设被用于数据库筛选过程。滑行得分，结合自由能 检查了药代动力学和药效学性质，以缩小筛选出的化合物的范围。该分析产生了命中分子DB03916，与具有毒性的参比化合物相比，该分子表现出更好的对接得分，更高的结合亲和力和更好的类药物特性。重要的是，使用50 ns的分子动力学模拟研究对结果进行了验证。总体而言，我们得出结论，认为所鉴定的命中分子DB03916可作为针对VPS34的前瞻性拮抗剂用于癌症治疗。与具有毒性的参比化合物相比，具有更高的结合亲和力和更好的药物样特性。重要的是，使用50 ns的分子动力学模拟研究对结果进行了验证。总体而言，我们得出结论，认为所鉴定的命中分子DB03916可作为针对VPS34的前瞻性拮抗剂用于癌症治疗。与具有毒性的参比化合物相比，具有更高的结合亲和力和更好的药物样特性。重要的是，使用50 ns的分子动力学模拟研究对结果进行了验证。总体而言，我们得出结论，认为所鉴定的命中分子DB03916可作为针对VPS34的前瞻性拮抗剂用于癌症治疗。