Designing new drug candidates as inhibitors against wild and mutant type neuraminidases: molecular docking, molecular dynamics and binding free energy calculations

Influenza virus is the cause of the death of millions of people with about 3–4 pandemics every hundred years in history. It also turns into a seasonal disease, bringing about approximately 5–15% of the population to be infected and 290,000–650,000 people to die every year. These numbers reveal that it is necessary to be on the alert to work towards influenza in order to protect public health. There are FDA-approved antiviral drugs such as oseltamivir and zanamivir recommended by the World Center for Disease Prevention. However, after the recent outbreaks such as bird flu and swine flu, increasing studies have shown that the flu virus has gained resistance to these drugs. So, there is an urgent need to find new drugs effective against this virus. This study aims to investigate new drug candidates targeting neuraminidase (NA) for the treatment of influenza by using computer aided drug design approaches. They involve virtual scanning, de novo design, rational design, docking, MD, MMGB/PBSA. The investigation includes H1N1, H5N1, H2N2 and H3N2 neuraminidase proteins and their mutant variants possessing resistance to FDA-approved drugs. Virtual screening consists of approximately 30 thousand molecules while de novo and rational designs produced over a hundred molecules. These approaches produced three lead molecules with binding energies for both non-mutant (-34.84, −59.99 and −60.66 kcal/mol) and mutant (-40.40, −58.93, −76.19 kcal/mol) H2N2 NA calculated by MM-PBSA compared with those of oseltamivir −25.64 and −18.40 respectively. The results offer new drug candidates against influenza infection. Communicated by Ramaswamy H. Sarma流感病毒（Influenza virus）是导致数百万人死亡的病原体，历史上每百年约暴发3-4次大流行。该病毒还会演变为季节性传染病，每年约造成5%至15%的人群感染，29万至65万人死亡。上述数据表明，为保障公众健康，需强化流感防控工作的警惕性。经美国食品药品监督管理局（Food and Drug Administration, FDA）批准的抗病毒药物，如奥司他韦（oseltamivir）、扎那米韦（zanamivir），已被世界疾病预防中心推荐使用。然而，在近期禽流感、猪流感等暴发事件后，越来越多的研究表明，流感病毒已对上述药物产生耐药性。因此亟需研发可有效对抗该病毒的新型药物。本研究旨在借助计算机辅助药物设计（computer aided drug design）方法，筛选靶向神经氨酸酶（neuraminidase, NA）的抗流感候选新药。该研究方案涵盖虚拟扫描、从头设计、理性设计、分子对接（docking）、分子动力学（Molecular Dynamics, MD）以及MMGB/PBSA计算分析。本次研究涵盖H1N1、H5N1、H2N2及H3N2型神经氨酸酶蛋白，以及对FDA批准药物具有耐药性的突变变体。虚拟筛选涉及约3万个分子，而从头设计与理性设计分别生成了百余个候选分子。通过MM-PBSA计算所得的结合能显示，针对野生型与突变型H2N2型神经氨酸酶，本研究获得的3个先导分子的结合能分别为：野生型H2N2 NA为-34.84、-59.99及-60.66 kcal/mol，突变型H2N2 NA为-40.40、-58.93及-76.19 kcal/mol；并与奥司他韦的对应结合能（分别为-25.64与-18.40 kcal/mol）进行了对比。本研究结果为抗流感感染提供了新型候选药物。本文由Ramaswamy H. Sarma转交刊发。