Also, in many countries (e

Also, in many countries (e.g., in Europe), millions of euros were spent in a myriad of fragmented projects but definitively not enough were dedicated to the development of in vitro screening platforms (i.e., the cost of developing such platforms to quickly test hypotheses is negligible as compared to the social and economic turmoil caused by the pandemic). the entire world economy and that is also devastating. SARS-CoV-2 is a coronavirus similar to SAR-CoV-1 (emerged in 2002) and MERS-CoV (emerged in 2012) that infect vertebrates. It is a large, F11R enveloped, single-stranded positive-sense RNA virus [1]. Its genome comprises several open reading frames (ORFs), two-thirds of which encode nonstructural proteins (Nsp) that make up the replicase complex. MK-0752 The remaining encodes nine accessory proteins (ORF) and four structural proteins: Spike (S), Envelope (E), Membrane (M), and Nucleocapsid (N), of which the Spike protein mediates entry into host cells via binding to the angiotensin-converting enzyme 2 MK-0752 (ACE2) receptor [2], [3], [4], [5], [6]. The Spike, an oligomeric transmembrane protein, can be cleaved and further activated by several enzymes [7], [8], including the host surface serine protease, TMPRSS2 [3] (Fig. 1). The severity of the host response depends on numerous factors, including an innate response to viral recognition [9], [10]. If the antiviral response is delayed or inhibited, viral proliferation can lead to the large-scale recruitment of neutrophils and monocyte-macrophages to the lungs, creating a hyper-inflammatory environment [10]. It has been found, in some COVID-19 patients, that there is an intense release of pro-inflammatory cytokines, i.e., cytokine storm (CS) [11], [12], [13], [14], and in some patients, rapid progression to Acute Respiratory Distress Syndrome can occur [15], [16], [17]. Open in a separate window Fig. 1 The virtual screening workflow for the identification and development of COVID-19 treatments using different drug discovery tools. This number was influenced by the study reported here [215]. Many different strategies can be used to determine disease prevention medicines and/or treatments. In the present context, considering the computer virus life cycle, one may aim at medicines acting at different phases of the illness (e.g., access, replication, and dissemination) [7], [18], [19], [20], [21], [22], [23], [24]. The medicines could be small chemical compounds and (stapled) peptides [21], [25], [26], [27], [28], [29], [30], [31], [32], restorative proteins including antibodies or nanobodies [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], vaccines [46], [47] and cells [48], [49], [50]. These medicines could interfere with the functioning of viral macromolecules and/or with the sponsor proteins and/or complex not fully understood molecular mechanisms and pathways (e.g., many cationic amphiphilic medicines take action on specific focuses on but also on endocytosis [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65]. As in all drug discovery project involving small molecules (but also often for other types of therapeutic providers), there are numerous ways to prioritize focuses on depending on the goal (hit one target, several focuses on inside a pathway) [66], [67], [68], [69], [70], [71], [72], [73], [74]. Once some focuses on are selected, experimental high-throughput and in silico screening can be performed. If 3D constructions are known or can be expected by homology modeling [75], [76], [77], a critical step for target prioritization usually entails the recognition of druggable or ligandable pouches (binding cavities, hot-spots, and cryptic sites) [78], [79], [80], [81], [82], [83], [84]. For SARS-CoV-2, major efforts have indeed been MK-0752 made in the field of structural biology (e.g., primarily X-ray and Cryo-EM considering the size MK-0752 of the macromolecules) [85] while homology modeling and related structural bioinformatics servers have in general launched a special services on Covid-19 (i.e., pages dedicated to SARS-CoV-2 protein prediction and/or analysis). Further, knowledge about the SARS-CoV-2/human being interactome is critical to assist MK-0752 the selection of focuses on and/or the finding of drug candidates [86], [87], [88], [89]. Comparisons with other viruses can obviously give important insights about the molecular mechanisms at play and about useful focuses on [90]. Taken collectively, about 20 proteins directly linked to the disease and involved at different phases of the SARS-CoV-2 computer virus life cycle could be druggable, including access into the sponsor cells (e.g., the viral Spike and the sponsor ACE2 and TMPRSS2 proteins), RNA replication, and transcription (e.g., helicase and RNA-dependent RNA polymerase (RdRp)), and translation and proteolytic control of viral proteins (e.g., viral main protease (Mpro), 3CLpro and the papain-like (PLpro) protease) (Fig. 1). Clearly, many other sponsor proteins and proteinCprotein relationships can also be regarded as (e.g., possibly the CD147-Spike interaction and a few hundred others). As mentioned above, developing (antiviral) medicines (from small.