KR20220025563A - Finding Potential Anti-COVID-19 Agents targeting Mpro Protein - Google Patents
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Abstract
본 발명은 Mpro 단백질을 저해하는 새로운 COVID-19 치료용 후보물질 발굴에 관한 것으로, 약효가능성 타진을 위하여 분자도킹계산과 자유에너지계산을 수행하였고 약물 타겟 단백질로는 COVID-19에 존재하는 Mpro(주요프로타아제, PDB ID: 6LU7) 단백질을 사용하였으며, 이에 대한 항코로나바이러스 활성을 가지는 물질을 기존에 승인된 약물에서 발굴하였다. 본 발명에 따르면 코로나바이러스에 대하여 Mpro(주요프로타아제, PDB ID: 6LU7) 단백질의 억제 활성을 갖고 있어 코로나바이러스의 예방 또는 치료용 약학적 조성물, 예방 또는 개선용 건강기능식품으로 유용하게 활용될 수 있다.The present invention relates to the discovery of new COVID-19 treatment candidates that inhibit Mpro protein, and molecular docking calculation and free energy calculation were performed to examine drug efficacy. As a drug target protein, Mpro present in COVID-19 (major Protase, PDB ID: 6LU7) protein was used, and a substance having anti-coronavirus activity against it was discovered from previously approved drugs. According to the present invention, it has inhibitory activity of Mpro (major protase, PDB ID: 6LU7) protein against coronavirus, so it can be usefully used as a pharmaceutical composition for the prevention or treatment of coronavirus, or as a health functional food for prevention or improvement. can
Description
본 발명은 Mpro 단백질을 저해하는 새로운 COVID-19(SARS-CoV-2) 치료용 후보물질 발굴에 관한 것이다.The present invention relates to the discovery of new COVID-19 (SARS-CoV-2) treatment candidates that inhibit Mpro protein.
일명 COVID-19(SARS-CoV-2) 바이러스는 2019년 중국 우한시에서 시작된 호흡기질환으로서, 코로나바이러스 감염으로 인한 질병으로 심한 호흡기증상을 나타내면서 감염환자의 상당수가 사망까지 이르게 되고 있다. 코로나바이러스 감염증에 대한 공인된 치료제로는 리바비린(ribavirin), 펜시클로비르(penclovir), 니타코사니드(nitazoxanide), 나파모스태트(nafamostat), 클로르퀴닌(chloroquinie)등이 알려져 있으며 이외에도 렘디시비르(GS-5734,remdesivir), 파비피라비르(favipiravir)가 코로나바이러스 감염증 치료에 사용되고 있으나 효과가 낮고 핵산아날로그형의 항바이러스제들의 특성상 변종바이러스의 발생율이 높아 2종이상의 항바이러스제를 같이 적용하고 있다.The so-called COVID-19 (SARS-CoV-2) virus is a respiratory disease that started in Wuhan, China in 2019. It is a disease caused by coronavirus infection and shows severe respiratory symptoms, leading to death of a significant number of infected patients. Remdisivir ( GS-5734, remdesivir) and favipiravir are used to treat coronavirus infection, but they are ineffective and have a high incidence of variant viruses due to the characteristics of nucleic acid analog antiviral agents, so two or more antiviral agents are being used together.
COVID-19 바이러스와 다른 코로나바이러스들의 근연률을 살펴보면, Rat coronavirus(Rat CoV)는 코로나바이러스의 일종으로 호흡기질환을 유발하는 바이러스이며, (Pravin N. Bhatt, Dean H. Percy, and Albert M. Jonas. Characterization of the Virus of Sialodacryoadenitis of Rats: A Member of the Coronavims Group. J. Infect Dis. 126(2): 123-130) Pubmed의 분석한 자료에 의하면 COVID-19 바이러스와는 65%의 단백질 서열 동일성과 77%의 유사성을 나타낸다. PEDV와 TGEV는 돼지에서 장염을 유발하는 코로나바이러스로 COVID-19 바이러스와는 각각 60,66%의 단백질 서열동일성과 75, 80%의 유사성을 나타내어 코로나바이러스들간의 단백질 서열에 상호 유사성이 매우 높다. 반면, 코로나바이어스와 같은 한가닥 RNA를 유전형으로 가지는 바이러스인 라이노바이러스는 22%의 단백질 서열 동일성과 39%의 유사성을 나타내어 단백질 서열 연관성에 있어서 코로나바이러스와의 유사성이 낮으며, 역시 한가닥 RNA를 유전형으로 가지는 바이러스인 인플루엔자바이러스도 28%의 단백질 서열 동일성과 34%의 유사성을 나타내어 코로나바이러스와의 유사성이 낮다. 이에 기존의 코로나바이러스와는 별개의 바이러스로 분류되어 이에 대한 치료 및 예방에 환한 이슈가 집중되고 있다.Looking at the kinship rate between the COVID-19 virus and other coronaviruses, the Rat coronavirus (Rat CoV) is a type of coronavirus that causes respiratory diseases (Pravin N. Bhatt, Dean H. Percy, and Albert M. Jonas). Characterization of the Virus of Sialodacryoadenitis of Rats: A Member of the Coronavims Group. J. Infect Dis. 126(2): 123-130) According to data analyzed by Pubmed, 65% protein sequence identity with COVID-19 virus and 77% similarity. PEDV and TGEV are coronaviruses that cause enteritis in pigs. They show 60,66% protein sequence identity and 75 and 80% similarity to COVID-19 virus, respectively, so the protein sequence between coronaviruses is very similar. On the other hand, rhinovirus, which is a virus having single-stranded RNA as a genotype such as coronavirus, exhibits 22% protein sequence identity and 39% similarity, showing low similarity to coronavirus in protein sequence association, and also uses single-stranded RNA as its genotype. Influenza virus, a virus with eggplant, also shows 28% protein sequence identity and 34% similarity, so the similarity to coronavirus is low. Therefore, it is classified as a virus separate from the existing coronavirus, and bright issues are focused on treatment and prevention.
리바비린을 비롯한 렘디시비르 등의 코로나바이러스 감염증에 사용되는 항바이러스제들은 대부분 RNA polymerase 억제능을 가지는 물질들이다. 다만, 렘디시비르에 대한 내성을 가진 코로나바이러스의 일종인 마우스 간염바이러스가 발견되었으며 기존의 항바이러스제의 효과가 없는 실정이다.Most of the antiviral agents used for coronavirus infection, such as ribavirin and remdisivir, are substances with RNA polymerase inhibitory activity. However, a mouse hepatitis virus, a type of coronavirus with resistance to remdisivir, has been found, and the existing antiviral agents have no effect.
또한, 현재까지 개발된 항바이러스들은 심한 부작용을 나타내고 있으므로, 그 응용에 있어서 많은 주의가 필요하다. 이러한 치료제는 효과적이지 못하며 부작용 또한 나타나고 있는 실정이다. 그러므로 코로나바이러스의 발생을 예방하고 치료하기 위한 감염 억제 효과가 뛰어나고 독성이 적은 우수한 새로운 코로나 바이러스제의 개발이 필요하다.In addition, since antiviruses developed to date exhibit severe side effects, much attention is required in their application. These treatments are not effective and side effects are also present. Therefore, there is a need for the development of an excellent novel coronavirus drug with excellent infection suppression effect and low toxicity to prevent and treat the outbreak of coronavirus.
이러한 배경 하에, 본 발명자들은, 컴퓨터신약설계(Computer-Aided Drug Design) 기법과 분자도킹기법을 활용하여 이 바이러스의 치료제를 발굴연구를 시도하였다. 개발 시간을 획기적으로 단축하기 위한 기존 약물 중에서 원하는 치료효과를 지닌 약물을 탐색하는 신약재창출(Drug Reposition) 연구기법을 이용하였다. 약효가능성 타진을 위하여 분자도킹계산과 자유에너지계산을 수행하였고 약물 타겟 단백질로는 COVID-19에 존재하는 Mpro(주요프로타아제, PDB ID: 6LU7) 단백질을 사용하였으며, 이에 대한 항코로나바이러스 활성을 가지는 물질을 기존에 승인된 약물에서 발굴함으로써, 본 발명을 완성하였다.Under this background, the present inventors attempted to discover and study a therapeutic agent for this virus by using a computer-aided drug design technique and a molecular docking technique. In order to dramatically shorten the development time, a new drug reposition research technique was used to search for a drug with a desired therapeutic effect among existing drugs. Molecular docking calculation and free energy calculation were performed to examine the drug efficacy, and Mpro (major protase, PDB ID: 6LU7) protein present in COVID-19 was used as the drug target protein, and anti-coronavirus activity against it was used. The present invention was completed by excavating a substance having a previously approved drug.
따라서, 본 발명의 목적은 Mpro(주요프로타아제, PDB ID: 6LU7) 단백질의 억제 활성을 갖는 화합물을 유효성분으로 포함하는 코로나바이러스 감염증 예방 또는 치료용 약학 조성물을 제공하는 데에 있다.Accordingly, an object of the present invention is to provide a pharmaceutical composition for preventing or treating coronavirus infection comprising a compound having an inhibitory activity of Mpro (major protase, PDB ID: 6LU7) protein as an active ingredient.
본 발명의 또 다른 목적은 Mpro(주요프로타아제, PDB ID: 6LU7) 단백질의 억제 활성을 갖는는 화합물을 유효성분으로 포함하는 코로나바이러스 감염증 예방 또는 개선용 건강식품 조성물을 제공하는 데에 있다.Another object of the present invention is to provide a health food composition for preventing or improving coronavirus infection comprising a compound having inhibitory activity of Mpro (major protase, PDB ID: 6LU7) protein as an active ingredient.
전술한 목적을 달성하기 위해 본 발명은, 블로난세린(Blonanserin), 플루나리진(Flunarizine) 또는 피마사르탄칼륨삼수화물(Fimasartan Potassium Trihydrate), 이들의 유도체 또는 이들의 염을 유효성분으로 포함하는 코로나바이러스 감염증 예방 또는 치료용 약학 조성물을 제공한다.In order to achieve the above object, the present invention includes, as an active ingredient, Blonanserin, Flunarizine or Fimasartan Potassium Trihydrate, derivatives thereof or salts thereof. It provides a pharmaceutical composition for preventing or treating coronavirus infection.
본 발명에 따르면 코로나바이러스에 대하여 Mpro(주요프로타아제, PDB ID: 6LU7) 단백질의 억제 활성을 갖고 있어 코로나바이러스의 예방 또는 치료용 약학적 조성물, 예방 또는 개선용 건강기능식품으로 유용하게 활용될 수 있다.According to the present invention, it has inhibitory activity of Mpro (major protase, PDB ID: 6LU7) protein against coronavirus, so it can be usefully used as a pharmaceutical composition for the prevention or treatment of coronavirus, or as a health functional food for prevention or improvement. can
도 1은 COVID-19 Mpro에 대한 잠재적인 약물후보물질을 발굴하기 위한 computational drug repurposing process 개요도를 나타낸 것이다. 도 2는 COVID-19 Mpro에 대한 약물후보물질의 분자도킹 스코어를 나타낸 것이다.1 shows a schematic diagram of a computational drug repurposing process for discovering potential drug candidates for COVID-19 Mpro. Figure 2 shows the molecular docking score of the drug candidate for COVID-19 Mpro.
이하, 본 발명의 바람직한 실시예를 첨부된 도면을 참고하여 보다 상세하게 설명하도록 한다.Hereinafter, preferred embodiments of the present invention will be described in more detail with reference to the accompanying drawings.
본 발명은 Mpro 단백질을 저해하는 새로운 COVID-19 (SARS-CoV-2) 치료용 후보물질 발굴에 관한 것이다.The present invention relates to the discovery of new COVID-19 (SARS-CoV-2) treatment candidates that inhibit Mpro protein.
본 발명의 일실시예에 따르면 Mpro(주요프로타아제, PDB ID: 6LU7) 단백질의 억제 활성을 갖는 화합물을 유효성분으로 포함하는 코로나바이러스 감염증 예방 또는 치료용 약학 조성물을 제공한다.According to an embodiment of the present invention, there is provided a pharmaceutical composition for preventing or treating coronavirus infection comprising a compound having an inhibitory activity of Mpro (major protase, PDB ID: 6LU7) protein as an active ingredient.
또한 본 발명의 일실시예에 따르면 Mpro(주요프로타아제, PDB ID: 6LU7) 단백질의 억제 활성을 갖는는 화합물을 유효성분으로 포함하는 코로나바이러스 감염증 예방 또는 개선용 건강식품 조성물을 제공한다.In addition, according to an embodiment of the present invention, it provides a health food composition for preventing or improving coronavirus infection comprising a compound having inhibitory activity of Mpro (major protase, PDB ID: 6LU7) protein as an active ingredient.
본 발명에 따르면 컴퓨터신약설계(Computer-Aided Drug Design) 기법과 분자도킹기법을 활용하여 이 바이러스의 치료제를 발굴연구를 시도하였다. 개발 시간을 획기적으로 단축하기 위한 기존 약물 중에서 원하는 치료효과를 지닌 약물을 탐색하는 신약재창출(Drug Reposition) 연구기법을 이용하였다. 약효가능성 타진을 위하여 분자도킹계산과 자유에너지계산을 수행하였고 약물 타겟 단백질로는 COVID-19에 존재하는 Mpro(주요프로타아제, PDB ID: 6LU7) 단백질을 사용하였으며, 이에 대한 항코로나바이러스 활성을 가지는 물질을 기존에 승인된 약물에서 발굴하였다.According to the present invention, an attempt was made to discover and study a therapeutic agent for this virus using a computer-aided drug design technique and a molecular docking technique. In order to dramatically shorten the development time, a new drug reposition research technique was used to search for a drug with a desired therapeutic effect among existing drugs. Molecular docking calculation and free energy calculation were performed to examine drug efficacy. As a drug target protein, Mpro (major protase, PDB ID: 6LU7) protein present in COVID-19 was used, and the anti-coronavirus activity against it was used. Substances with eggplant were discovered from previously approved drugs.
본 발명은 FDA에서 승인된 1865개의 약물 데이터를 대상으로 COVID-19 (SARS-CoV 2) 치료제 가능성 여부를 조사하였다. 한국화학연구원(KRICT)에서 KCB-DR DB로부터 약물데이터를 받아서 1865개 전체 약물데이터와 Mpro 단백질과의 분자도킹모의실험을 실시하여 149개를 1차로 선별하고, 정밀분석을 통하여 3개를 물질을 도출하였다(도 1).The present invention investigated the possibility of a treatment for COVID-19 (SARS-CoV 2) targeting 1865 drug data approved by the FDA. The Korea Research Institute of Chemical Technology (KRICT) received drug data from the KCB-DR DB and conducted a molecular docking simulation with 1865 total drug data and Mpro protein to select 149 first, and 3 substances through precise analysis. derived (Fig. 1).
구체적으로 본 발명에서는 3개의 후보물질로서, 블로난세린(Blonanserin), 플루나리진(Flunarizine) 또는 피마사르탄칼륨삼수화물(Fimasartan Potassium Trihydrate), 이들의 유도체 또는 이들의 염을 유효성분으로 포함하는 코로나바이러스 감염증 예방 또는 치료용 약학 조성물을 제공한다.Specifically, in the present invention, as three candidate substances, Blonanserin, Flunarizine, or Fimasartan Potassium Trihydrate, derivatives thereof, or salts thereof are included as active ingredients. It provides a pharmaceutical composition for preventing or treating coronavirus infection.
본 발명에서 설명되는 후보물질은 아래 표 1에 표시하였다.Candidate substances described in the present invention are shown in Table 1 below.
본 발명에서 발굴될 후보물질의 Goldscore 및 Chemscore를 확인하였으며, 대조군으로 기준 화합물인 N3, Lopinavir, Ritonavir 등 3개 약물을 사용하였다. 사용 결과 기존의 화합물에 비하여 높은 분자도킹 스코어를 가지는 것으로 나타났다(도 2).The Goldscore and Chemscore of the candidate material to be discovered in the present invention were confirmed, and three drugs such as N3, Lopinavir, and Ritonavir, which are reference compounds, were used as controls. As a result of use, it was found to have a higher molecular docking score than that of the conventional compound (FIG. 2).
본 발명의 블로난세린(Blonanserin)은 하기 화학식 1로 표시될 수 있다.Blonanserin of the present invention may be represented by the following formula (1).
[화학식 1][Formula 1]
또한, 본 발명의 플루나리진(Flunarizine)은 하기 화학식 2로 표시될 수 있다.In addition, flunarizine of the present invention may be represented by the following formula (2).
[화학식 2][Formula 2]
또한, 본 발명의 피마사르탄칼륨삼수화물(Fimasartan Potassium Trihydrate)은 하기 화학식 3으로 표시될 수 있다.In addition, the fimasartan potassium trihydrate of the present invention may be represented by the following formula (3).
[화학식 3][Formula 3]
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| WO2024130411A1 (en) * | 2022-12-21 | 2024-06-27 | Variational Ai Inc. | Protease inhibitors and methods of using same |
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