Pharmacology Division, Department of Pharmacy and Pharmacology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 2193, South Africa; WITS Research Institute for Malaria (WRIM), Faculty of Health Sciences, University of Witwatersrand, Johannesburg, 2193, South Africa.
Council for Scientific and Industrial Research (CSIR), Future Production: Chemicals Cluster, Meiring Naude Road, Brummeria, Pretoria, 0001, South Africa.
J Mol Graph Model. 2022 Jan;110:108054. doi: 10.1016/j.jmgm.2021.108054. Epub 2021 Oct 15.
Organophosphates (OPs) used as potent insecticides for malaria vector control, covalently phosphorylate the catalytic serine residue of Anopheles gambiae AChE (AgAChE) in a reaction that liberates their leaving groups. In the recent 10-year insecticide use assessment, OPs were the most frequently used World Health Organization prequalified insecticides. Molecular modelling programs are best suited to display molecular interactions between ligands and the target proteins. The docking modes that generate ligand poses closer to the binding site show high accuracy in predicting the ligand binding mode. The implicit solvation approach such as molecular mechanics-generalized born surface area (MM-GBSA) is a more reliable method to predict ligand onformations and binding affinities. Apart from covalent docking studies being scarce, current molecular docking programs do not adequately possess the covalent docking reaction algorithm to display the molecular mechanism of OPs at the AgAChE catalytic site. This results into OP docking studies commonly being conducted through noncovalent pannels. The aim of this study was to establish the optimim covalent docking system for OPs through manual customization of Schrödinger's Glide covalent docking reaction algorithm. To achieve this, a newly customized covalent reaction algorithm was assessed on a set of ligands covering aromatic, non-aromatic and hydrophobic OPs and compared to the noncovalent docking results in terms of reliability based on the reported X-ray diffraction molecular interactions and crystal poses. The study established that by virtue of omitting the well-known OP hydrolysis, noncovalent mode suggested molecular interactions that were further from the catalytic triad and could not otherwise occur when the molecule is hydrolyzed as in the customized covalent docking mode. Moreover, the MM-GBSA concurred with the optimized covalent docking in eliminating such inaccurate molecular interactions. Additionally, the covalent docking mode confined the interactions and ligand poses to the catalytic site indicating relatively high accuracy and reliability. This study reports the optimized covalent docking panel that effectively confirmed the molecular mechanisms of OPs, as well as indentifying the corresponding amino acid residues required to stabilize the aromatic, non-aromatic and hydrophobic OPs at the AgAChE catalytic site in line with the reported X-ray diffraction studies. As such, the proposed manual customization of the Schrödinger's Glide covalent docking platform can be used to reliably predict molecular interactions between OPs and AgAChE target.
有机磷化合物（OPs）作为强力杀虫剂，用于疟疾媒介控制，与冈比亚按蚊乙酰胆碱酯酶（AgAChE）的催化丝氨酸残基共价结合，释放其离去基团。在最近的十年杀虫剂使用评估中，OPs 是世界卫生组织最常使用的合格杀虫剂。分子建模程序最适合显示配体和靶蛋白之间的分子相互作用。产生更接近结合部位的配体构象的对接模式显示出在预测配体结合模式方面的高精度。隐式溶剂化方法（如分子力学-广义 Born 表面积（MM-GBSA））是预测配体构象和结合亲和力的更可靠方法。除了共价对接研究相对较少之外，当前的分子对接程序也没有充分具备共价对接反应算法，无法在 AgAChE 催化部位显示 OPs 的分子机制。这导致 OP 对接研究通常通过非共价对接进行。本研究的目的是通过对手册定制 Schrödinger 的 Glide 共价对接反应算法，建立 OPs 的最佳共价对接系统。为了实现这一目标，评估了一组涵盖芳香族、非芳香族和疏水性 OPs 的配体，根据报道的 X 射线衍射分子相互作用和晶体构象，基于可靠性比较了新定制的共价反应算法与非共价对接结果。研究结果表明，通过省略众所周知的 OP 水解，非共价模式建议的分子相互作用与催化三联体进一步远离，并且当分子如在定制的共价对接模式中水解时，不能发生这种情况。此外，MM-GBSA 与优化的共价对接一致，消除了这种不准确的分子相互作用。此外，共价对接模式将相互作用和配体构象限制在催化部位，表明相对较高的准确性和可靠性。本研究报告了有效的优化共价对接面板，该面板有效地证实了 OPs 的分子机制，并确定了与报道的 X 射线衍射研究一致的稳定 AgAChE 催化部位的芳香族、非芳香族和疏水性 OPs 所需的相应氨基酸残基。因此，可以使用 Schrödinger 的 Glide 共价对接平台的这种手动定制来可靠地预测 OPs 和 AgAChE 靶之间的分子相互作用。
