Pharmaceuticals for Targeting Coronaviruses

Luciana Scotti, Marcus T. Scotti

• Éditeur: Bentham Science Publishers
• Année: 2001
• ISBN:
  9789815051308
• Sujet: Medicine
• Sous-sujet: Pharmacology

This reference summarizes information about pharmaceuticals that can target infectious strains of coronaviruses to neutralize infections. Chapters focus on SARS-CoV-2, drug discovery methods and natural methods to combat the virus, which is a causative agent of COVID-19. Specifically, the book presents 5 chapters written by expert scholar on the following topics: Structure-Based Drug Discovery Approaches Applied to SARS-CoV-2 (the causative agent COVID- 19)
Potential Antiviral Medicinal Plants against Novel SARS-CoV-2
Infections Caused by SARS Coronaviruses: Main Characteristics, Targets And Inhibitors
Natural Sourced Traditional Indian and Chinese Medicines to Combat COVID- 19
Peptidomimetic and Peptide-Derived Agents Against 3CLpro from Coronaviruses The book contents present both conventional drug design and traditional approaches to discovering relevant drugs in an easy-to-read approach, which is supplemented by bibliographic references. It is intended as a reference for students (pharmacology, pharmacy) and researchers (virology) who are seeking information about antiviral drugs that can be used against coronaviruses.

Structure-Based Drug Discovery Approaches Applied to SARS-CoV-2 (COVID-19)

Igor José dos Santos Nascimento¹, Thiago Mendonça de Aquino¹, Edeildo Ferreira da Silva-Júnior^{1, 2, *}

¹ Chemistry and Biotechnology Institute, Federal University of Alagoas, Maceió, Brazil

² Laboratory of Medicinal Chemistry, Pharmaceutical Sciences Institute, Federal University of Alagoas, Maceió, Brazil

Abstract

Viral diseases have caused millions of deaths around the world. In the past, health organizations and pharmaceutical industries have neglected these diseases for years, mainly because they affected a small geographic population. In contrast, since 2016, several viral outbreaks have been reported worldwide, such as those caused by Ebola, Zika, and SARS-CoV2 (COVID-19). Thus, these have received more attention, leading to increased efforts to search for new antiviral drugs. The SARS-CoV-2 pandemic, already responsible for more than 1,254,567 deaths worldwide, is the greatest example of a virus that has always been present in our society, responsible for small outbreaks in Asian and Arabic countries in 2004 and 2012. But, investments in research to identify/discover new drugs and vaccines were only intensified in 2020, in which only the remdesivir (an FDA-approved drug) was developed to addressCOVID-19 until today. Nonetheless, it has been used in hospitals in the United States and Japan, in emergency cases. Indeed, it justifies greater investments in discovering new alternatives that could save thousands of people. In this context, improving drug discovery techniques is fundamental in searching for new therapies that could be selective and effective to combat SARS-CoV-2. Drug discovery approaches are based on ligands (Ligand-Based Drug Design - LBDD) or structures (Structure-Based Drug Discovery - SBDD). Concerning SBDD, it is the main and most evolved technique used for discovering new drugs. The application of SBDD techniques has improved the pharmacological arsenal against diverse diseases, which allowed the discovery of innovative treatments, such as inhibitors of HIV-1 proteases. In this chapter, main SBDD techniques (i.e. homology modeling; molecular dynamics and docking; de novo drug discovery; pharmacophore modeling; fragment-based drug discovery; and virtual high-throughput screenings) applied to discover new hit compounds SARS-CoV-2 (COVID-19) will be discussed in details.

Keywords: Drug discovery, Dynamics simulations, Molecular modeling, SARS-CoV-2, Structure-Based Drug Discovery, TMPRSS2, Virtual screening.

---

^* Corresponding author Edeildo Ferreira da Silva-Júnior: Chemistry and Biotechnology Institute, Federal University of Alagoas, Maceió, Brazil and Laboratory of Medicinal Chemistry, Pharmaceutical Sciences Institute, Federal University of Alagoas, Maceió, Brazil; Tel: [phone]; E-mail: [email protected]

1. Introduction

On December 31^st, 2019, an outbreak of pneumonia was reported caused by an unknown etiologic agent in Wuhan, a province of Hubei in China. Thus, with the sporadic number of cases, on January 9^th, 2020, the new coronavirus was recognized as the causative agent by the Chinese Center for Disease Control and Prevention (CDC). When it started spreading at an alarming pace to other countries in the world, the new coronavirus (SARS-CoV-2, or COVID-19) was declared a pandemic by the world health organization (WHO) on March 11^th, 2020 [1^-3].

Since its discovery, SARS-CoV-2 has been responsible for several victims worldwide. To date (09/11/2020), there are already 50,266,033 confirmed cases with 1,254,567 deaths [4]. The main symptoms are fever, cough, fatigue, myalgia, and dyspnea. Its transmission occurs mainly through coughing, sneezing, and respiratory droplets [5]. These alarming statistics make research groups from around the world focus on discovering new therapies against this pandemic virus [6]. Advances in drug developments resulted in the repurposing of remdesivir in the United States. However, this drug still does not show the best effectiveness. So, a molecule that could be effective in eliminating SARS-CoV2 from the body is an unmet needed [6, 7].

Currently, biological targets guide the process of discovering new drugs. Then, the structure of a macromolecule is fundamental for this process [8]. Such structures provide valuable information on mechanisms of action and their correlation with biological activity [9]. In addition, information about the biological target and the availability of three-dimensional structures for these therapeutically attractive targets have resulted in several advances in the identification of inhibitors, as well as potential binding sites, contributing to the basis of structure-based drug discovery strategies (SBDD) [10].

In addition, in silico methods are increasingly gaining more visibility in the drug development field. These methods are used in SBDD and are related to higher chances of success with less financial cost and less time-consuming [11, 12].

In this context, this chapter will be addressed to the main SBDD techniques (homology modeling; molecular docking and dynamic; pharmacophore modeling; virtual screening and virtual high-throughput screening; fragment-based drug design; and de novo drug design) applied for the discovery of new promising compounds against SARS-CoV2.

2. Coronaviruses: History and Structure

Coronaviridae is a family of several groups of viruses responsible for the infection of both animals and humans. From this family, there are seven viruses that can infect humans, being: Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV); Middle East Respiratory Syndrome Coronavirus (MERS-CoV); Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2); HCoV-OC43; HCoV-KHU1; HCoV-NL63; HCoV-229E [13]. Among these, the first three belong to the genus Betacoronavirus, and all of them display high potential for mutability, leading to plasticity and genetic variability, which contributes to their adaptation to different types of hosts [13, 14].

The first discovery of SARS-CoV was around the 1960s [15]. This pathogen is related to flu-like symptoms. However, its progress generates respiratory failure and, in many cases, death since it presents a higher mortality rate [16]. The SARS-CoV is a virus from animal reservoirs (in this case, bats) that can spread to other animals and humans, initially reported in Guangdong (China), in 2002 [16^-18]. One year later, it spread to Asia and America, affecting 26 nations and causing 8,000 deaths. After its control, other reports were associated with laboratory accidents or transmission from animals to humans [16].

Concernin...