Maira Riaz, Azam Muhammad, Irfan Ahmed, Basra Muhammad Asim Raza
School of Chemistry, University of the Punjab, New Campus Lahore-54590, Punjab, Pakistan.
Department of Chemistry, College of Science, King Khalid University, Abha, Saudi Arabia.
J Mol Model. 2025 Aug 26;31(9):257. doi: 10.1007/s00894-025-06483-9.
Computational approaches are instrumental in understanding the structural and electronic characteristics of drug metal complexes, thereby facilitating the rational deign of more effective pharmaceutical agents prior to experimental validation. The present work was designed to evaluate the drug-likeness and therapeutic potential, bioavailability, pharmacokinetics, and toxicity characteristics of piroxicam transition metal (Mn, Fe, Co, Ni, and Zn). Additionally, the comprehensive structural, electronic, and solvent-dependent behavior were investigated through theoretical analysis, with particular emphasis geometry optimizations and stabilization effects explored in solvents such as water, ethanol, and DMSO. Among the studied systems, the Co and Ni-piroxicam complexes exhibited the highest stabilization energy. HOMO-LUMO energy gaps and molecular electrostatic potential (MEP) maps indicate enhanced charge transfer characteristics, helping to identify reactive electrophilic and nucleophilic sites. These findings underscore the significant influence of solvent polarity and metal ion size on the physicochemical properties and potential bioavailability of metal drug complexes. The ADMET assessment also proved the safety profile coupled with no predicted toxicity, offering meaningful insights for rational drug design.
ADMET analysis was carried out using the ADMETlab 3.0 online web server to predict, pharmacokinetic behavior, and various toxicity aspects. Furthermore, the geometry optimization and frequency analyses were performed using DFT at the B3LYP/6-31G(d,p) level for non-metal atoms and SDD basis set for transition metals. Solvent effects (water, ethanol, and DMSO) were modeled using the SMD continuum model as implemented in the Gaussian 16. Key descriptors such as HOMO-LUMO energies, their energy gaps, molecular electrostatic potential (ESP), and thermodynamics metrics were computed by Multiwf, Jmol, and SHERMO, respectively.
计算方法有助于理解药物金属配合物的结构和电子特性，从而在实验验证之前促进更有效药物制剂的合理设计。本研究旨在评估吡罗昔康过渡金属（锰、铁、钴、镍和锌）的药物相似性、治疗潜力、生物利用度、药代动力学和毒性特征。此外，通过理论分析研究了其全面的结构、电子和溶剂依赖性行为，特别强调了在水、乙醇和二甲基亚砜等溶剂中探索的几何优化和稳定化效应。在所研究的体系中，钴和镍-吡罗昔康配合物表现出最高的稳定能。最高占据分子轨道-最低未占据分子轨道（HOMO-LUMO）能隙和分子静电势（MEP）图表明电荷转移特性增强，有助于识别反应性亲电和亲核位点。这些发现强调了溶剂极性和金属离子大小对金属药物配合物物理化学性质和潜在生物利用度的重大影响。ADMET评估还证明了其安全性，且无预测毒性，为合理药物设计提供了有意义的见解。
使用ADMETlab 3.0在线网络服务器进行ADMET分析，以预测药代动力学行为和各种毒性方面。此外，使用密度泛函理论（DFT）在B3LYP/6-31G(d,p)水平对非金属原子进行几何优化和频率分析，对过渡金属使用 Stuttgart-Dresden-Düsseldorf（SDD）基组。使用高斯16中实现的导体屏蔽模型（SMD）连续介质模型对溶剂效应（水、乙醇和二甲基亚砜）进行建模。分别通过Multiwf、Jmol和SHERMO计算关键描述符，如HOMO-LUMO能量、它们的能隙、分子静电势（ESP）和热力学指标。
