Pharmacophore modeling, 2D-QSAR, molecular docking and ADME studies for the discovery of inhibitors of PBP2a in MRSA

Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) is considered to be a worldwide threat to human health and the global spread of MRSA has been associated with the emergence of different types of infections and resultant selection pressure due to exposure to many antibiotics. In the current era characterized by incessant antibiotic resistance, assessment of multiple molecular targets represents notable therapeutic opportunities in the medical and pharmaceutical industry and can aid in the discovery of novel molecules that inhibit various receptors effectively to replace the current weak antimicrobial agents. Penicillin binding protein 2a (PBP2a) of MRSA is a major determinant of resistance to β-lactam antibiotics. The activity of PBP2a is not inhibited by β-lactam antibiotics, allowing the strain to survive in the presence of β-lactams leading to resistance to β-lactam antibiotics. The study aimed at identifying potential inhibitors of PBP2a receptor of MRSA through ligand-based pharmacophore modeling, 2D-QSAR, molecular docking, ADMET screening as well as molecular dynamic (MD) simulations. The study led to the development of a satisfactory, predictive and significant 2D-QSAR model for predicting anti-MRSA activity of compounds and also led to the identification of two molecules: C₂₁H₂₅N₇O₄S₂ (ChEMBL30602) and C₂₀H₁₇NO₆S (ChEMBL304837) with favorable pharmacophore features and ADME properties with potential to bind strongly to PBP2a receptor of MRSA. MD simulation analysis showed that the interactions of C₂₀H₁₇NO₆S (ChEMBL304837) with PBP2a over 100 ns was more stable and similar to the interaction of ceftobiprole with PBP2a and may become potential drug candidate against MRSA which has developed a lot of resistance to current antibiotics.

甲氧西林耐药金黄色葡萄球菌（MRSA）被视为对人类健康的全球性威胁，其全球传播与多种感染的出现以及因接触多种抗生素而产生的选择压力密切相关。在当前抗生素耐药性持续蔓延的时代，对多种分子靶点的评估为医药行业带来了重要的治疗契机，有助于开发能够有效抑制各类受体的新型分子，以替代当前疗效欠佳的抗菌药物。MRSA的青霉素结合蛋白2a（PBP2a）是其对β-内酰胺类抗生素产生耐药性的主要决定因素：β-内酰胺类抗生素无法抑制PBP2a的活性，使得该菌株在β-内酰胺类抗生素存在的环境下仍可存活，进而产生对该类抗生素的耐药性。本研究通过基于配体的药效团建模、二维定量构效关系（2D-QSAR）、分子对接、ADMET（吸收、分布、代谢、排泄、毒性）筛选以及分子动力学（MD）模拟，旨在筛选出MRSA的PBP2a受体潜在抑制剂。研究结果不仅成功构建了性能优异、预测性良好且具有统计学意义的2D-QSAR模型，用于预测化合物的抗MRSA活性，还筛选得到两个候选分子：C₂₁H₂₅N₇O₄S₂（ChEMBL30602）与C₂₀H₁₇NO₆S（ChEMBL304837），二者具备良好的药效团特征与ADME（吸收、分布、代谢、排泄）性质，能够与MRSA的PBP2a受体紧密结合。分子动力学模拟分析显示，C₂₀H₁₇NO₆S（ChEMBL304837）与PBP2a在100纳秒内的结合相互作用更为稳定，且与头孢托罗（ceftobiprole）和PBP2a的结合模式相似，有望成为针对当前多数抗生素已产生耐药性的MRSA的潜在候选药物。