Munsamy Geraldene, Ramharack Pritika, Soliman Mahmoud E S
Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal Westville Campus Durban 4001 South Africa
RSC Adv. 2018 Jun 13;8(39):21829-21840. doi: 10.1039/c8ra04360d.
Plasmepsins, a family of aspartic proteases expressed by parasite, have been identified as key mediators in the onset of lethal malaria. Precedence has been placed on this family of enzymes due their essential role in the virulence of the parasite, thus highlighting their importance as novel drug targets. A previously published study by our group proposed a set of parameters used to define the flap motion of aspartic proteases. These parameters were used in the study of Plm I-V and focused on the flap flexibility as well as structural dynamics. Recent studies have highlighted the essential role played by Plm IX and X in egress and invasion of the malarial parasite. This study aims to close the gap on the latter family, investigating the flap dynamics of Plms IX and X. Molecular dynamics simulations demonstrated an "open and close" mechanism at the region of the catalytic site. Further computation of the dihedral angles at the catalytic region revealed tractability at both the flap tip and flexible loop. This structural versatility enhances the interaction of variant ligand sizes, in comparison to other Plm family members. The results obtained from this study signify the essential role of structural flap dynamics and its resultant effect on the binding landscapes of Plm IX and X. We believe that this unique structural mechanism may be integrated in the design and development of effective anti-malarial drugs.
疟原虫天冬氨酸蛋白酶（plasmepsins）是由寄生虫表达的一类天冬氨酸蛋白酶，已被确定为致命疟疾发病的关键介质。由于这类酶在寄生虫毒力中起关键作用，所以受到了重视，这突出了它们作为新型药物靶点的重要性。我们团队之前发表的一项研究提出了一组用于定义天冬氨酸蛋白酶瓣片运动的参数。这些参数被用于研究Plm I-V，并聚焦于瓣片灵活性以及结构动力学。最近的研究突出了Plm IX和X在疟原虫逸出和入侵过程中所起的关键作用。本研究旨在填补对后一类研究的空白，研究Plm IX和X的瓣片动力学。分子动力学模拟在催化位点区域显示出一种“打开和关闭”机制。对催化区域二面角的进一步计算揭示了瓣片尖端和柔性环处的易处理性。与其他Plm家族成员相比，这种结构多样性增强了与不同大小配体的相互作用。本研究获得的结果表明了结构瓣片动力学的关键作用及其对Plm IX和X结合态势的影响。我们相信，这种独特的结构机制可用于有效抗疟药物的设计和开发。
