Recent advances in automated protein design and its future challenges

Setiawan, Dani; Brender, Jeffrey R.; Zhang, Yang

doi:10.1080/17460441.2018.1465922

Cited by 24 publications

(17 citation statements)

References 197 publications

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“…Indeed, the use of a single protein structure in SBDD implies accepting the outdated lock-and-key model as the unique recognition process between protein and ligands. In contrast, considering the conformational diversity of a protein may improve the probability succeeding in discovering novel active compounds (Setiawan et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological Activity

González

Cardama

Chinestrad

et al. 2020

Front. Cell Dev. Biol.

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In the last years, the development of new drugs in oncology has evolved notably. In particular, drug development has shifted from empirical screening of active cytotoxic compounds to molecularly targeted drugs blocking specific biologic pathways that drive cancer progression and metastasis. Using a rational design approach, our group has developed 1A-116 as a promising Rac1 inhibitor, with antitumoral and antimetastatic effects in several types of cancer. Rac1 is over activated in a wide range of tumor types and and it is one of the most studied proteins of the Rho GTPase family. Its role in actin cytoskeleton reorganization has effects on endocytosis, vesicular trafficking, cell cycle progression and cellular migration. In this context, the regulatory activity of Rac1 affects several key processes in the course of the cancer including invasion and metastasis. The purpose of this preclinical study was to focus on the mode of action of 1A-116, conducting an interdisciplinary approach with in silico bioinformatics tools and in vitro assays. Here, we demonstrate that the tryptophan 56 residue is necessary for the inhibitory effects of 1A-116 since this compound interferes with protein-protein interactions (PPI) of Rac1GTPase involving several GEF activators. 1A-116 is also able to inhibit the oncogenic Rac1 P29S mutant protein, one of the oncogenic drivers found in sun-exposed melanoma. It also inhibits numerous Rac1-regulated cellular processes such as membrane ruffling and lamellipodia formation. These results deepen our knowledge of 1A-116 inhibition of Rac1 and its biological impact on cancer progression. They also represent a good example of how in silico analyses represent a valuable approach for drug development.

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Section: Introductionmentioning

confidence: 99%

Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological Activity

González

Cardama

Chinestrad

et al. 2020

Front. Cell Dev. Biol.

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“…Moreover, the usage of these tools in EvoProDom provides a general method to obtain protein domain content and orthologous protein annotation. This method may be applicable to other research fields such as proteomics (9), protein design (10) and host-virus interactions (11). Thus, EvoProDom presents a novel model for protein evolution based on “mix and merge” of protein domains rather than DNA based models.…”

Section: Discussionmentioning

confidence: 99%

“…By applying these protein sequence-based methods to obtain protein domain content and orthologous protein annotation, new organisms were easily added to EvoProDom. Moreover, this method is unique to EvoProDom and is applicable to other protein domain-based applications such as proteomics (9), protein design (10) and host-virus interactions (11).…”

Section: Methodsmentioning

confidence: 99%

“…We presented in EvoProDom, a general method to obtain protein domain content and orthologous protein annotation, by predicting these data from protein sequences using the Pfam search tool (6, 7) and KoFamKOALA (8), respectively. This method can be implemented in other research fields such as proteomics (9), protein design (10) and host-virus interactions (11).…”

Section: Introductionmentioning

confidence: 99%

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EvoProDom: Evolutionary model of protein families by means of translocations of protein domains

Carmi

Gorohovski

Frenkel‐Morgenstern

2020

Preprint

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† These authors contributed equally to this work. AbstractHere, we developed a novel evolution of protein domains (EvoProDom) model for evolution of proteins, which was based on mix and merge of protein domains. We collected and integrated genomic and proteome data for 109 organisms. These data include protein domain content and orthologous protein families. In EvoProDom, we defined evolutionary events, such as translocations, as reciprocal exchanges of protein domains between orthologous proteins of different organisms. We found that protein domains, which frequently appear in translocation events, were enriched in trans-splicing events, i.e., producing novel transcripts fused from two distinct genes. We presented in EvoProDom, a general method to obtain protein domain content and orthologous protein annotation, by predicting these data from protein sequences using the Pfam search tool and KoFamKOALA, respectively. This method can be implemented in other research such as proteomics, protein design and host-virus interactions.We hypothesized that proteins evolve by means of "mix and merge" or "shuffling" of 113 protein domains, which are distinct functional units (1, 20). The evolutionary model that 114 7 described protein evolution by means of protein domain dynamics was termed 115EvoProDom. The EvoProDom model defined and formulated standard evolutionary 116 mechanisms such as translocations, duplications and indel (insertion and deletion) events, 117 which acted on protein domains that were realized as Pfam domains (6, 7). Therefore, 118proteins, under the EvoProDom model, gained or lost their function based on the 119 presence or absence of respective function-conferring domains. Accordingly, proteins 120 were modeled as sets of protein domains; and evolutionary events, such as translocations, 121 were defined. These describe the gain and loss of particular domains between domain sets 122 or DAs. The KEGG database catalogs diverse taxa and forms groups of orthologous 123 proteins (KO) based on shared function. Thus, all members of the KO group were 124 orthologous proteins (8, 12, 13). Additionally, in the EvoProDom model, proteins were 125 assigned to KO groups (see Materials and Methods). Consequently, translocation events 126 were mapped to groups of organisms according to underlying changes in DA. Thus, 127 evolutionary events, which acted upon domains and manifested as changes in DA were 128 reflected at the organism level. A link between changes at these two levels was therefore 129 established. The EvoProDom model was implemented with and tested on EvoProDomDB 130 (see Materials and Methods). In total, 5,548 translocation events, involving 94 protein 131 super families, excluding an "unknown" super family, were found ( Table 2). This result 132 indicates the existence of multiple evolutionary translocation events as defined by the 133 model. 134Mapping of genes to proteins and alternative splicing 135 EvoProDom combined genomic information (genes) with proteins, and in turn, proteins 136 with Pfam doma...

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“…EvoProDom, devised as a general method to obtain orthologous protein annotation and protein domain content, is based on predictions of these data from protein sequences using KoFamKOALA [6] and the Pfam search tool [7,8], respectively. The method used for designed EvoProDom can be implemented in other research fields, from closely related fields such as proteomics [9], protein design [10] and far as assessing PPI in host-virus systems [11].…”

Section: Accepted Articlementioning

confidence: 99%

EvoProDom: evolutionary modeling of protein families by assessing translocations of protein domains

2021

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Here, we introduce a novel "evolution of protein domains" (EvoProDom) model for describing the evolution of proteins based on the "mix and merge" of protein domains. We assembled and integrated genomic and proteomic data comprising protein domain content and orthologous protein content from 109 organisms. In EvoProDom, we characterized evolutionary events, e.g., translocations, as reciprocal exchanges of protein domains between orthologous proteins in different organisms. We showed that protein domains that translocate with highly frequency are generated by transcripts enriched in trans-splicing events, i.e., the generation of novel transcripts from the fusion of two distinct genes. In EvoProDom, we describe a general method to define orthologous protein annotation and protein domain content by predicting these traits from protein sequences using tools such as KoFamKOAL and the Pfam search tool, respectively. In conclusion, EvoProDom presents a novel model for protein evolution based on the "mix and merge" view of protein domains rather than DNAbased models. This confers the advantage of considering chromosomal alterations in evolutionary events.

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Recent advances in automated protein design and its future challenges

Cited by 24 publications

References 197 publications

Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological Activity

Computational and in vitro Pharmacodynamics Characterization of 1A-116 Rac1 Inhibitor: Relevance of Trp56 in Its Biological Activity

EvoProDom: Evolutionary model of protein families by means of translocations of protein domains

EvoProDom: evolutionary modeling of protein families by assessing translocations of protein domains

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