Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.
J Mol Model. 2021 Jan 9;27(2):35. doi: 10.1007/s00894-020-04663-3.
Compound P131 has been established to inhibit Cryptosporidium parvum's inosine monophosphate dehydrogenase (CpIMPDH). Its inhibitory activity supersedes that of paromomycin, which is extensively used in treating cryptosporidiosis. Through the per-residue energy decomposition approach, crucial moieties of P131 were identified and subsequently adopted to create a pharmacophore model for virtual screening in the ZINC database. This search generated eight ADMET-compliant hits that were examined thoroughly to fit into the active site of CpIMPDH via molecular docking. Three compounds ZINC46542062, ZINC58646829, and ZINC89780094, with favorable docking scores of - 8.3 kcal/mol, - 8.2 kcal/mol, and - 7.5 kcal/mol, were selected. The potential inhibitory mechanism of these compounds was probed using molecular dynamics simulation and Molecular Mechanics Generalized Poisson Boltzmann Surface Area (MM/PBSA) analyses. Results revealed that one of the hits (ZINC46542062) exhibited a lower binding free energy of - 39.52 kcal/mol than P131, which had - 34.6 kcal/mol. Conformational perturbation induced by the binding of the identified hits to CpIMPDH was similar to P131, suggesting a similarity in inhibitory mechanisms. Also, in silico investigation of the properties of the hit compounds implied superior physicochemical properties with regards to their synthetic accessibility, lipophilicity, and number of hydrogen bond donors and acceptors in comparison with P131. ZINC46542062 was identified as a promising hit compound with the highest binding affinity to the target protein and favorable physicochemical and pharmacokinetic properties relative to P131. The identified compounds can serve as a basis for conducting further experimental investigations toward the development of anticryptosporidials, which can overcome the challenges of existing therapeutic options. Graphical abstract P131 and the identified compounds docked in the NAD binding site of Cryptosporidium parvum IMPDH.
化合物 P131 已被证实可抑制微小隐孢子虫肌苷单磷酸脱氢酶（CpIMPDH）。其抑制活性超过了广泛用于治疗隐孢子虫病的巴龙霉素。通过残基能量分解方法，确定了 P131 的关键部分，并随后采用该方法创建了一个针对 ZINC 数据库中虚拟筛选的药效团模型。该搜索生成了 8 个符合 ADMET 标准的命中化合物，通过分子对接对其进行了全面检查，以适合 CpIMPDH 的活性部位。三个化合物 ZINC46542062、ZINC58646829 和 ZINC89780094 的对接评分分别为-8.3 kcal/mol、-8.2 kcal/mol 和-7.5 kcal/mol，具有良好的对接评分。使用分子动力学模拟和分子力学广义泊松-玻尔兹曼表面面积（MM/PBSA）分析方法对这些化合物的潜在抑制机制进行了探究。结果表明，其中一个命中化合物（ZINC46542062）的结合自由能比 P131 低-39.52 kcal/mol，P131 的结合自由能为-34.6 kcal/mol。与 P131 相似，鉴定出的命中化合物与 CpIMPDH 结合后，构象发生了扰动，这表明它们的抑制机制相似。此外，对命中化合物性质的计算机研究表明，与 P131 相比，它们在合成可及性、脂溶性、氢键供体和受体数量方面具有更好的物理化学性质。与 P131 相比，ZINC46542062 被确定为一种很有前途的命中化合物，它与靶蛋白的结合亲和力最高，且具有良好的物理化学和药代动力学性质。鉴定出的化合物可以作为进一步开展抗隐孢子虫药物开发实验研究的基础，这可以克服现有治疗方案的挑战。
