Molecular dynamics simulation of the antifungal N-((5-cyclopropylisoxazol-3-yl)methyl)-3-(2,3-dihydrobenzofuran-5-yl)-N-methylbenzamide binding to Cryptococcus neoformans acetyl CoA synthetase CnAcs1

The molecule, referred to as isoxazole 1, was identified in a high throughput screen for antifungal inhibitors of Cryptococcus neoformans acetyl CoA synthetase using a synthetic lethal phenotypic screen. The Xray crystal structure of the molecule was determined. Molecular dynamics simulations were performed to study the interactions of the inhibitor with the target. Three independent simulations are included in this data set using the Desmond module of Schrodinger software (Schrodinger, LLC, New York, NY, 2024-1) with OPLS 4 force field (56). First, the molecular system of the ligand-receptor complex was built with water molecules in a cubic box via the simple point charge (SPC) method; which was later followed by ions neutralization by the addition of sodium, to balance the net charge of the solvated system. MD simulation was performed for 1000 ns using the Isothermal-isobaric (NPT) ensemble class, where temperature and pressure were reserved at 300 K and 1.01325 bar pressure employing Nose-Hoover temperature coupling and isotropic scaling. Equilibration of the systems and MD simulations were carried out using the default protocol provided in Desmond本研究中的目标分子被命名为异恶唑1（isoxazole 1），通过合成致死表型筛选策略，在针对新型隐球菌（Cryptococcus neoformans）乙酰辅酶A合成酶的抗真菌抑制剂高通量筛选中被成功鉴定。该分子的X射线晶体结构已被解析。为探究该抑制剂与靶点的相互作用，本研究开展了分子动力学模拟。本数据集包含三组独立的模拟结果，采用Schrödinger软件（Schrödinger有限责任公司，纽约州纽约市，2024-1版）的Desmond模块完成，模拟体系使用OPLS 4力场（参考文献56）。首先，通过简单点电荷（SPC）模型，在立方盒子中构建配体-受体复合物的分子体系，随后添加钠离子进行电荷中和，以平衡溶剂化体系的净电荷。随后采用等温等压（NPT）系综进行时长1000 ns的分子动力学模拟，模拟过程中将温度与压力分别维持在300 K与1.01325巴，并使用Nosé-Hoover温度耦合方案与各向同性压力缩放算法。体系平衡与分子动力学模拟均采用Desmond内置的默认流程完成。