School of Pharmaceutical Sciences, Universiti Sains Malaysia, George Town 11800, Malaysia.
Pharmaceutical Design and Simulation (PHDS) Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, George Town 11800, Malaysia.
Molecules. 2021 Aug 31;26(17):5304. doi: 10.3390/molecules26175304.
Drug targeting is a progressive area of research with folate receptor alpha (FRα) receiving significant attention as a biological marker in cancer drug delivery. The binding affinity of folic acid (FA) to the FRα active site provides a basis for recognition of FRα. In this study, FA was conjugated to beta-cyclodextrin (βCD) and subjected to in silico analysis (molecular docking and molecular dynamics (MD) simulation (100 ns)) to investigate the affinity and stability for the conjugated system compared to unconjugated and apo systems (ligand free). Docking studies revealed that the conjugated FA bound into the active site of FRα with a docking score (free binding energy < -15 kcal/mol), with a similar binding pose to that of unconjugated FA. Subsequent analyses from molecular dynamics (MD) simulations, root mean square deviation (RMSD), root mean square fluctuation (RMSF), and radius of gyration (Rg) demonstrated that FA and FA-βCDs created more dynamically stable systems with FRα than the apo-FRα system. All systems reached equilibrium with stable RMSD values ranging from 1.9-2.4 Å and the average residual fluctuation values of the FRα backbone atoms for all residues (except for terminal residues ARG8, THR9, THR214, and LEU215) were less than 2.1 Å with a consistent Rg value of around 16.8 Å throughout the MD simulation time (0-100 ns). The conjugation with βCD improved the stability and decreased the mobility of all the residues (except residues 149-151) compared to FA-FRα and apo-FRα systems. Further analysis of H-bonds, binding free energy (MM-PBSA), and per residue decomposition energy revealed that besides APS81, residues HIS20, TRP102, HIS135, TRP138, TRP140, and TRP171 were shown to have more favourable energy contributions in the holo systems than in the apo-FRα system, and these residues might have a direct role in increasing the stability of holo systems.
药物靶向是一个不断发展的研究领域，叶酸受体 alpha（FRα）作为癌症药物输送中的生物标志物受到了广泛关注。叶酸（FA）与 FRα 活性位点的结合亲和力为 FRα 的识别提供了基础。在这项研究中，FA 被共轭到β-环糊精（βCD）上，并进行了计算机分析（分子对接和分子动力学（MD）模拟（100 ns）），以研究与未共轭和apo 系统（无配体）相比，共轭系统的亲和力和稳定性。对接研究表明，共轭 FA 与 FRα 的活性位点结合，具有 docking score（自由结合能< -15 kcal/mol），与未共轭 FA 的结合构象相似。随后的分子动力学（MD）模拟分析，均方根偏差（RMSD）、均方根波动（RMSF）和回转半径（Rg）表明，与 apo-FRα 系统相比，FA 和 FA-βCDs 与 FRα 形成了更动态稳定的系统。所有系统都达到了平衡，具有稳定的 RMSD 值范围为 1.9-2.4 Å，并且所有残基的 FRα 骨架原子的平均残基波动值（除了末端残基 ARG8、THR9、THR214 和 LEU215）都小于 2.1 Å，整个 MD 模拟时间（0-100 ns）的 Rg 值约为 16.8 Å。与 FA-FRα 和 apo-FRα 系统相比，βCD 的共轭提高了所有残基（除了残基 149-151）的稳定性和降低了它们的流动性。进一步分析氢键、结合自由能（MM-PBSA）和每残基分解能表明，除了 APS81 之外，残基 HIS20、TRP102、HIS135、TRP138、TRP140 和 TRP171 在全同系统中比在 apo-FRα 系统中表现出更有利的能量贡献，这些残基可能在增加全同系统的稳定性方面发挥直接作用。
