Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, Natal 59072-970, Rio Grande do Norte, Brazil.
Departamento de Física Teórica e Experimental, Universidade Federal do Rio Grande do Norte, Natal 59072-970, Rio Grande do Norte, Brazil.
J Phys Chem B. 2021 Dec 2;125(47):12972-12980. doi: 10.1021/acs.jpcb.1c07298. Epub 2021 Nov 18.
Envenomation via snakebites occurs largely in areas where it is harder to access the hospital. Its mortality rate and sequelae acquired by the survivors symbolize a big challenge for antivenom therapy. In particular, the homologous phospholipase A (Lys49-PLA) proteins can induce myonecrosis and are not effectively neutralized by current treatments. Thus, by taking advantage of crystallographic structures of Lys49-PLA complexed with VRD (varespladib) and AIN (aspirin), a quantum biochemistry study based on the molecular fractionation with conjugate cap scheme within the density functional theory formalism is performed to unveil these complexes' detailed interaction energies. The calculations revealed that important interactions between ligands and the Lys49-PLA pocket could occur up to a pocket radius of = 6.5 (5.0 Å) for VRD (AIN), with the total interaction energy of the VRD ligand being higher than that of the AIN ligand, which is well-correlated with the experimental binding affinity. Furthermore, we have identified the role played by the amino acids LYS0069, LYS0049, LEU0005, ILE0009, CYS0029, GLY0030, HIS0048, PRO0018, ALA0019, CYS0045, TYR0052, TYR0022, PRO0125*, and PHE0126* (LYS0069, LYS0049, GLY0032, LEU0002, and LEU0005) in the VRD↔Lys49-PLA (AIN↔Lys49-PLA) complex. Our simulations are a valuable tool to support the big challenge for neutralizing the damages in victims of snakebites.
蛇咬伤中毒主要发生在难以获得医院治疗的地区。其死亡率和幸存者遗留的后遗症对抗蛇毒治疗构成了巨大挑战。特别是同源的磷脂酶 A（Lys49-PLA）蛋白可引起肌肉坏死，且目前的治疗方法无法有效中和。因此，利用 Lys49-PLA 与 VRD（varespladib）和 AIN（aspirin）复合物的晶体结构，基于密度泛函理论形式中的共轭帽方案的分子分馏进行量子生物化学研究，以揭示这些复合物的详细相互作用能。计算表明，配体与 Lys49-PLA 口袋之间的重要相互作用可以发生在 VRD（AIN）的口袋半径 = 6.5（5.0 Å）范围内，VRD 配体的总相互作用能高于 AIN 配体，这与实验结合亲和力很好地相关。此外，我们确定了氨基酸 LYS0069、LYS0049、LEU0005、ILE0009、CYS0029、GLY0030、HIS0048、PRO0018、ALA0019、CYS0045、TYR0052、TYR0022、PRO0125和 PHE0126（LYS0069、LYS0049、GLY0032、LEU0002 和 LEU0005）在 VRD↔Lys49-PLA（AIN↔Lys49-PLA）复合物中的作用。我们的模拟是支持对抗蛇咬伤受害者损害的中和这一巨大挑战的有价值工具。
