标题：Characterization of fenugreek and its natural compounds targeting AKT-1 protein in cancer: Pharmacophore, virtual screening, and MD simulation techniques
摘要：AbstractObjectiveCancer is the second biggest cause of death in humans. Rapid advancements in clinical bioinformatics and high-throughput proteomics technology are essential tools and methodologies for cancer research. Medicinal plants are considered operative therapeutic agents that are utilized for novel drug discovery and development, using computer-aided drug design (CAAD). The AKT-1 Serine/Threonine Kinase family was chosen as the target protein because it is implicated in the mediation of the cancer process. In this work, phytocompounds that target AKT-1 in cancer were recognized and were used to identify their binding relationship with the nominated receptor.MethodsA dried extraction of Fenugreek (Trigonella foenum-graecum) seeds in solid form was obtained using an evaporation technique and phytochemicals present in it were tested using qualitative tests. Fenugreek and its natural components were evaluated against AKT-1 because chemical agents acquired from natural sources appear to be particularly appealing alternatives to synthetic compounds. Different bioinformatics computational methods were used for protein structural analysis, interactive comparison, alignment, and superposition of AKT-1 protein structures in 3D. By using molecular docking and molecular dynamic (MD) simulation experiments, the binding interaction of the selected compounds with AKT-1 was investigated.ResultsFenugreek seeds yielded by phytochemicals screening and crude extractions of tannins, saponin, steroids, and cardiac glycosides were found to have very high antioxidant activity. After virtual screening hits, the top three phytocompounds (Compound-1 tannins, Compound-2 saponins, and Compound-3 steroids) were selected against AKT-1 on the basis of their strong binding energy (−10.9 to −9.2 Kcal/mol). Compound-1 showed the highest pharmacophore fit score (43.91) among all compounds. In molecular interactions, some crucial residues (Gln-79, Trp-80, Thr-82, Val-270, Tyr-272, Asp-274, and Asp-292) were observed at binding pockets of AKT-1. MD simulations at 100 ns revealed that the ligand was bound to the protein with some major conformational changes in the protein structure.ConclusionsIn-silicostudies report new dimensions for novel drug design targeting AKT-1. The three leading hits inhibit the cancer cell's inflammation activity in the AKT-1 pathway. In the future, these three compounds might be tested for the drug discovery of inflammatory disorders.
