Abstract
The emergence in late 2019 of the coronavirus SARS-CoV-2 has resulted in the breakthrough of the COVID-19 pandemic that is presently affecting a growing number of countries. The development of the pandemic has also prompted an unprecedented effort of the scientific community to understand the molecular bases of the virus infection and to propose rational drug design strategies able to alleviate the serious COVID-19 morbidity. In this context, a strong synergy between the structural biophysics and molecular modeling and simulation communities has emerged, resolving at the atomistic level the crucial protein apparatus of the virus and revealing the dynamic aspects of key viral processes. In this Review, we focus on how in silico studies have contributed to the understanding of the SARS-CoV-2 infection mechanism and the proposal of novel and original agents to inhibit the viral key functioning. This Review deals with the SARS-CoV-2 spike protein, including the mode of action that this structural protein uses to entry human cells, as well as with nonstructural viral proteins, focusing the attention on the most studied proteases and also proposing alternative mechanisms involving some of its domains, such as the SARS unique domain. We demonstrate that molecular modeling and simulation represent an effective approach to gather information on key biological processes and thus guide rational molecular design strategies.
Highlights
A new coronavirus, which emerged in China at the end of 2019 and was soon named SARS-CoV-2, was recognized as the causative agent of severe acute respiratory syndrome (SARS) that in some cases evolved into severe pneumonia.[1−3] Later, it was recognized that SARS-CoV-2 was able to cross the interspecies barrier[4] and was characterized by a high transmissibility between humans.[5]
Oligopeptides present several advantages with respect to traditional small drugs: (i) They cover large surfaces of the binding hot spots through multiple contacts, (ii) the interactions are based on protein− protein recognition and are highly specific, (iii) because they are based on human angiotensin converting enzyme 2 (ACE2) sequences, they are unlikely to trigger unwanted immune responses, and (iv) they can be potentially combined with nanoparticle carriers.[153]
Molecular modeling and simulation techniques have achieved a high degree of maturity that allows their use to answer key biological questions, especially concerning rational drug design development
Summary
A new coronavirus, which emerged in China at the end of 2019 and was soon named SARS-CoV-2, was recognized as the causative agent of severe acute respiratory syndrome (SARS) that in some cases evolved into severe pneumonia.[1−3] Later, it was recognized that SARS-CoV-2 was able to cross the interspecies barrier[4] and was characterized by a high transmissibility between humans.[5]. The design of oligopeptides based on ACE2 sequences and able to bind to the RBD has been recently proposed to selectively target the viral material.[151,152] Oligopeptides present several advantages with respect to traditional small drugs: (i) They cover large surfaces of the binding hot spots through multiple contacts, (ii) the interactions are based on protein− protein recognition and are highly specific, (iii) because they are based on human ACE2 sequences, they are unlikely to trigger unwanted immune responses, and (iv) they can be potentially combined with nanoparticle carriers.[153] By using extended MD simulations, Han and Kraĺ 151 have studied four peptides based on the ACE2 PD (see Figure 7A−E), analyzed their stabilities through the root-mean-square deviation (RMSD) values (Figure 7F), and assessed their ability to bind SARS-CoV-2 RBD by estimating the binding energies (Figure 7G). Agents aiming at perturbing this interaction, enhancing the host defenses against the virus
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