Computational screening of chemical constituents derived from berry fruits as allosteric caspace-3/-7 inhibitors

IF 2.6 4区 生物学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY 3 Biotech Pub Date : 2024-09-16 DOI:10.1007/s13205-024-04067-7
Waseem Ahmad Ansari, Mohsin Ali Khan, S. M. Mahfooz Hasan, Zainab Siddiqui, Saheem Ahmad, Mohd Shahnawaz Khan, Mohammad Faheem Khan
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Abstract

With the aim of finding the plant-derived allosteric inhibitors of caspase-3/-7, we conducted computational investigations of bioactive compounds present in various berry fruits. In a molecular docking study, perulactone demonstrated excellent binding affinity scores of −12.1 kcal/mol and −9.1 kcal/mol for caspase 7 and 3, respectively, whereas FDA-approved allosteric inhibitors (DICA and FICA) were found to show lower docking scores (−5.6 and −6.1 kcal/mol) against caspase 7 while (−5.0 and −5.1 kcal/mol) for caspase 3, respectively. MD simulations were used to validate the binding stability of perulactone in the active sites of caspase-7/-3, and the results showed outstanding stability with lower ligand RMSDs of 1.270–3.088 Å and 2.426–9.850 Å against the targeted receptor. Furthermore, we performed MMGBSA free binding energy, where the perulactone values of ΔGBind were determined to be −63.98 kcal/mol and −66.32 kcal/mol for both receptors (3IBF and 1NME), which are significantly better than the −45.16 kcal/mol and −39.51 kcal/mol for DICA as well as −26.37 kcal/mol and −15.50 kcal/mol for FICA, respectively. The drug resemblance of perulactone was effectively evaluated by ADMET. Thus, our findings indicated that perulactone could be an orally administered therapeutic candidate for regulating apoptosis in a variety of disorders. However, there may be an urgent need to study using in vitro and in vivo experiments.

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计算筛选从浆果中提取的化学成分作为同工酶 Caspace-3/-7 抑制剂
为了找到源自植物的 Caspase-3/-7 异位抑制剂,我们对各种浆果中的生物活性化合物进行了计算研究。在分子对接研究中,perulactone 与 caspase 7 和 caspase 3 的结合亲和力得分分别为 -12.1 kcal/mol 和 -9.1 kcal/mol,而 FDA 批准的异位抑制剂(DICA 和 FICA)与 caspase 7 的对接得分较低(-5.6 和 -6.1 kcal/mol),与 caspase 3 的对接得分分别为 -5.0 和 -5.1 kcal/mol。我们利用 MD 模拟验证了 perulactone 在 caspase-7/-3 活性位点的结合稳定性,结果显示其具有出色的稳定性,与目标受体的配体 RMSD 值较低,分别为 1.270 至 3.088 Å 和 2.426 至 9.850 Å。此外,我们还进行了 MMGBSA 自由结合能测定,结果显示两种受体(3IBF 和 1NME)的 Perulactone ΔGBind 值分别为 -63.98 kcal/mol 和 -66.32 kcal/mol,明显优于 DICA 的 -45.16 kcal/mol 和 -39.51 kcal/mol 以及 FICA 的 -26.37 kcal/mol 和 -15.50 kcal/mol。通过 ADMET 有效评估了 Perulactone 的药物相似性。因此,我们的研究结果表明,秘鲁内酯可作为一种口服候选疗法,用于调节多种疾病的细胞凋亡。不过,目前可能还迫切需要进行体外和体内实验研究。
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来源期刊
3 Biotech
3 Biotech Agricultural and Biological Sciences-Agricultural and Biological Sciences (miscellaneous)
CiteScore
6.00
自引率
0.00%
发文量
314
期刊介绍: 3 Biotech publishes the results of the latest research related to the study and application of biotechnology to: - Medicine and Biomedical Sciences - Agriculture - The Environment The focus on these three technology sectors recognizes that complete Biotechnology applications often require a combination of techniques. 3 Biotech not only presents the latest developments in biotechnology but also addresses the problems and benefits of integrating a variety of techniques for a particular application. 3 Biotech will appeal to scientists and engineers in both academia and industry focused on the safe and efficient application of Biotechnology to Medicine, Agriculture and the Environment.
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