University of Abobo Adjamé, Laboratoire de Physique Fondamentale et Appliquée, 02 BP 801, Abidjan 02, Cote D'Ivoire.
Med Chem. 2012 Sep;8(5):970-84. doi: 10.2174/157340612802084324.
We have studied inhibition of Plasmodium falciparum lactate dehydrogenase (pfLDH) by dihydroxynaphthoic acid (DHNA) analogues derivatives of hemigossypol-sesquiterpene found in cottonseed known to exhibit antimalarial activity. Molecular models of pfLDH-DHNA complexes were prepared from high-resolution crystal structures containing DHNA and azole inhibitors and binding affinities of the inhibitors were computed by molecular mechanics - polarizable continuum model of solvation (MM-PCM) approach. The 3D structures of the pfLDH-DHNA complexes were validated by a QSAR model, which confirmed consistency between the computed binding affinities and experimental inhibition constants for a training set and validation set of twelve DHNA inhibitors obtained from literature. Novel more potent DHNA analogs were identified by structure-based molecular design and predicted to inhibit pfLDH in the low nanomolar concentration range. In addition, the designed DHNA analogs displayed favorable predicted ADME-related profiles and an elevated selectivity for the pfLDH over the human isoform.
我们研究了二羟萘酸（DHNA）类似物对半乳糖半棉酚-倍半萜（存在于棉籽中，具有抗疟活性）的抑制作用对恶性疟原虫乳酸脱氢酶（pfLDH）的抑制作用。从含有 DHNA 和唑类抑制剂的高分辨率晶体结构中制备了 pfLDH-DHNA 复合物的分子模型，并通过分子力学-极化连续模型的溶剂化（MM-PCM）方法计算了抑制剂的结合亲和力。通过 QSAR 模型验证了 pfLDH-DHNA 复合物的 3D 结构，该模型证实了从文献中获得的十二种 DHNA 抑制剂的训练集和验证集的计算结合亲和力与实验抑制常数之间的一致性。通过基于结构的分子设计鉴定了新型更有效的 DHNA 类似物，并预测它们将以低纳摩尔浓度范围抑制 pfLDH。此外，设计的 DHNA 类似物显示出有利的预测 ADME 相关特征，并且对 pfLDH 的选择性高于人同工酶。
