Padariya Monikaben, Kalathiya Umesh
Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, Narutowicza St 11/12, 80-233 Gdansk, Poland.
Gen Physiol Biophys. 2017 Apr;36(2):141-154. doi: 10.4149/gpb_2016028. Epub 2016 Dec 6.
Human immunodeficiency virus type 1 protease is a viral-encoded enzyme and it is essential for replication and assembly of the virus. Inactivation of HIV-1 protease causes production of immature, noninfectious viral particles and thus HIV-1 protease is an attractive target in anti-AIDS drug design. In our current work, we performed molecular dynamics (MD) calculations (500 ns) for two different ligands (COM5 - designed in our previous study, and Darunavir) and made effort to understand dynamics behaviour of our designed compound COM5. An apo form of HIV-1 protease as monomer and dimer form was also studied in order to analyze response of protein to the ligand. MD results suggest that presence of ligand in hinders the stability of HIV-1 protease and one monomer from dimer systems is dominant on other monomer in terms of interaction made with ligands. We were able to trace functional residues as well as continuous motion of opening and closing (clapping) of flap region in HIV-1 protease (apo form) during entire 1000 ns of MD simulation. COM5 showed almost similar behaviour towards HIV-1 protease enzyme as Darunavir and propose as promising lead compound for the development of new inhibitor for HIV-1 protease.
人类免疫缺陷病毒1型蛋白酶是一种病毒编码的酶，对病毒的复制和组装至关重要。HIV-1蛋白酶的失活会导致产生不成熟的、无感染性的病毒颗粒，因此HIV-1蛋白酶是抗艾滋病药物设计中一个有吸引力的靶点。在我们目前的工作中，我们对两种不同的配体（COM5——我们之前研究中设计的，以及达芦那韦）进行了分子动力学（MD）计算（500纳秒），并努力了解我们设计的化合物COM5的动力学行为。还研究了HIV-1蛋白酶的单体和二聚体形式的无配体形式，以分析蛋白质对配体的反应。MD结果表明，配体的存在会阻碍HIV-1蛋白酶的稳定性，并且在与配体的相互作用方面，二聚体系统中的一个单体比另一个单体占主导地位。在整个1000纳秒的MD模拟过程中，我们能够追踪HIV-1蛋白酶（无配体形式）中功能性残基以及瓣区打开和关闭（拍打）的连续运动。COM5对HIV-1蛋白酶的表现几乎与达芦那韦相似，并被提议作为开发新型HIV-1蛋白酶抑制剂的有前景的先导化合物。
