CROMATIC: Cross-Relationship Map of Cavities from Coronaviruses

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19 disease, has rapidly imposed an urgent need to identify effective drug candidates. In this context, the high resolution and non-redundant beta-Coronavirus protein cavities database is pivotal to help virtual screening protocols. Furthermore, the cross-relationship among cavities can lead to highlighting multitarget therapy chances. Here, we first collect all protein cavities on SARS-CoV-2, SARS-CoV, and MERS-CoV X-ray structures, and then, we compute a similarity map by using molecular interaction fields (MIFs). All the results come together in CROMATIC (CROss-relationship MAp of CaviTIes from Coronaviruses). CROMATIC encloses both a comprehensive and a non-redundant version of the cavities collection and a similarity map revealing, on the one hand, cavities that are conserved among the three Coronaviruses and, on the other hand, unexpected similarities among cavities that can represent a key starting point for multitarget therapy strategies. Similarity analysis was also performed for the available structures of SARS-CoV-2 spike variants, linking sequence mutations to three-dimensional interaction alterations. The CROMATIC repository is freely available to the scientific community at .

Recent advances in the molecular design and applications of proteolysis targeting chimera-based multi-specific antiviral modality

“…Moreover, developments in structural biology focusing on antiviral drug targets and computational chemistry (e.g., prediction of ternary complexes) will greatly facilitate the design of PROTAC antiviral molecules. Recent advances with a focus on SARS-CoV-2 indicate that computational simulations have a significant role in the design of PROTACs and their potential targets [89][90][91][92]. Furthermore, because obtaining a co-crystal structure from experiments is generally very time-consuming, the computational modeling approaches detailed in recent work [93][94][95][96][97][98][99][100], especially the modeling of PROTACmediated ternary complexes, could be utilized to design PROTACs for novel targets and optimize PROTACs for current targets so that the many advantages of a PROTAC-based degradation approach can be effectively utilized both rapidly and at reduced cost.…”

Strigolactones as Broad-Spectrum Antivirals against β-Coronaviruses through Targeting the Main Protease Mpro

“…EDOT-EGO and TH-EGO were evaluated by means of a structure-based virtual screening approach against all cavities of a database composed of 67 proteins and 124 corresponding pockets. 14 The FLAP structurebased approach 28 was applied to evaluate the molecular interaction field (MIF) complementarity between the template molecule and the cavity MIFs. The MIF superposition is reported as a complementarity score: the higher the score, the better the ligand fits into the cavity.…”

“…Conversely, SLs do not exhibit efficacy when inoculated during the adsorption stage (Figure 3C, panel ii), providing further evidence that a late step of β-CoV replication is targeted by SLs. To investigate which SARS-CoV-2 protein could be targeted by the analyzed SLs, we screened both SLs toward all the structures of coronavirus proteins present in CROMATIC at the time of the analyses, 14 using the screening procedure that allows evaluating the possible interaction of a series of ligands with several protein pockets. Overall, a total amount of 67 proteins and 124 pockets, belonging to the viruses MERS-CoV, SARS-CoV-1, and SARS-CoV-2, were considered.…”

“…Overall, a total amount of 67 proteins and 124 pockets, belonging to the viruses MERS-CoV, SARS-CoV-1, and SARS-CoV-2, were considered. 14 Pockets were ranked according to the Glob-Prod score and selected for having a score higher than 1.…”

Exploring the Fatty Acid Binding Pocket in the SARS-CoV-2 Spike Protein – Confirmed and Potential Ligands

“…When targeting the direct interaction between the RBD and ACE2, there is an intrinsic challenge, as the receptor binding motifs are highly variable at the sequence level . Nevertheless, since it is effective in reducing viral fitness, research focusing on blocking the interaction has resulted in numerous virtual screening campaigns targeting the S protein since the pandemic started. − Given the S protein size (∼1300 residues), variety of functions (from cell recognition to cell fusion), and conformational changes, the area selected for such analyses can vary significantly, with studies focusing only on the RBD, larger portions of the S protein, and searches for additional potential binding cavities. ,− …”