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Computer-Aided Design of α-L-Rhamnosidase to Increase the Synthesis Efficiency of Icariside I.

ABSTRACT: Icariside I, the glycosylation product of icaritin, is a novel effective anti-cancer agent with immunological anti-tumor activity. However, very limited natural icariside I content hinders its direct extraction from plants. Therefore, we employed a computer-aided protein design strategy to improve the catalytic efficiency and substrate specificity of the α-L-rhamnosidase from Thermotoga petrophila DSM 13995, to provide a highly-efficient preparation method. Several beneficial mutants were obtained by expanding the active cavity. The catalytic efficiencies of all mutants were improved 16-200-fold compared with the wild-type TpeRha. The double-point mutant DH was the best mutant and showed the highest catalytic efficiency (k _cat /K _M : 193.52 s^-1 M^-1) against icariin, which was a 209.76-fold increase compared with the wild-type TpeRha. Besides, the single-point mutant H570A showed higher substrate specificity than that of the wild-type TpeRha in hydrolysis of different substrates. This study provides enzyme design strategies and principles for the hydrolysis of rhamnosyl natural products.

SUBMITTER: Huang JJ

PROVIDER: S-EPMC9253678 | biostudies-literature |

REPOSITORIES: biostudies-literature

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A computer-guided design tool to increase the efficiency of cellular conversions

Project description:Here we introduce a computer-guided design tool that combines a computational framework for prioritizing more efficient combinations of instructive factors (IFs) of cellular conversions, called IRENE, with a transposon-based genomic integration system for efficient delivery. Particularly, IRENE relies on a stochastic gene regulatory network model that systematically prioritizes more efficient IFs by maximizing the agreement of the transcriptional and epigenetic landscapes between the converted and target cells. Our predictions substantially increased the efficiency of two established iPSC-differentiation protocols (natural killer cells and melanocytes) and established the first protocol for iPSC-derived mammary epithelial cells with high efficiency.

2021-02-02 | GSE165961 | GEO

Computer-Aided Design and Synthesis of (Functionalized quinazoline)–(α-substituted coumarin)–arylsulfonate Conjugates against Chikungunya Virus

Project description:Chikungunya virus (CHIKV) has repeatedly spread via the bite of an infected mosquito and affected more than 100 countries. The disease poses threats to public health and the economy in the infected locations. Many efforts have been devoted to identifying compounds that could inhibit CHIKV. Unfortunately, successful clinical candidates have not been found yet. Computations through the simulating recognition process were performed on complexation of the nsP3 protein of CHIKV with the structures of triply conjugated drug lead candidates. The outcomes provided the aid on rational design of functionalized quinazoline-(α-substituted coumarin)-arylsulfonate compounds to inhibit CHIKV in Vero cells. The molecular docking studies showed a void space around the β carbon atom of coumarin when a substituent was attached at the α position. The formed vacancy offered a good chance for a Michael addition to take place owing to steric and electronic effects. The best conjugate containing a quinazolinone moiety exhibited potency with EC50 = 6.46 μM, low toxicity with CC50 = 59.7 μM, and the selective index (SI) = 9.24. Furthermore, the corresponding 4-anilinoquinazoline derivative improved the anti-CHIKV potency to EC50 = 3.84 μM, CC50 = 72.3 μM, and SI = 18.8. The conjugate with 4-anilinoquinazoline exhibited stronger binding affinity towards the macro domain than that with quinazolinone via hydrophobic and hydrogen bond interactions.

| S-EPMC9322071 | biostudies-literature

Bioprinting of Multimaterials with Computer-aided Design/Computer-aided Manufacturing.

Project description:Multimaterials deposition, a distinct advantage in bioprinting, overcomes material's limitation in hydrogel-based bioprinting. Multimaterials are deposited in a build/support configuration to improve the structural integrity of three-dimensional bioprinted construct. A combination of rapid cross-linking hydrogel has been chosen for the build/support setup. The bioprinted construct was further chemically cross-linked to ensure a stable construct after print. This paper also proposes a file segmentation and preparation technique to be used in bioprinting for printing freeform structures.

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Computer-aided antibody design.

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Computer-Aided Drug Design in Epigenetics.

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| S-EPMC5857607 | biostudies-literature

A computer-guided design tool to increase the efficiency of cellular conversions.

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| S-EPMC7954801 | biostudies-literature

Computer aided design of FtsZ targeting oligopeptides†.

Project description:FtsZ is a protein involved in the bacterial division process and is thus an emerging target for antibacterial drugs. The network of interactions between FtsZ monomers necessary for exploitation of its biological function are studied here with molecular dynamics and free energy calculations. The results obtained led to the design of FtsZ targeting peptides which exhibited activity against the function of FtsZ in vitro.

| S-EPMC6217974 | biostudies-literature

Computer-Aided Ligand Discovery for Estrogen Receptor Alpha.

Project description:Breast cancer (BCa) is one of the most predominantly diagnosed cancers in women. Notably, 70% of BCa diagnoses are Estrogen Receptor ? positive (ER?+) making it a critical therapeutic target. With that, the two subtypes of ER, ER? and ER?, have contrasting effects on BCa cells. While ER? promotes cancerous activities, ER? isoform exhibits inhibitory effects on the same. ER-directed small molecule drug discovery for BCa has provided the FDA approved drugs tamoxifen, toremifene, raloxifene and fulvestrant that all bind to the estrogen binding site of the receptor. These ER-directed inhibitors are non-selective in nature and may eventually induce resistance in BCa cells as well as increase the risk of endometrial cancer development. Thus, there is an urgent need to develop novel drugs with alternative ER? targeting mechanisms that can overcome the limitations of conventional anti-ER? therapies. Several functional sites on ER?, such as Activation Function-2 (AF2), DNA binding domain (DBD), and F-domain, have been recently considered as potential targets in the context of drug research and discovery. In this review, we summarize methods of computer-aided drug design (CADD) that have been employed to analyze and explore potential targetable sites on ER?, discuss recent advancement of ER? inhibitor development, and highlight the potential opportunities and challenges of future ER?-directed drug discovery.

| S-EPMC7352601 | biostudies-literature

Toward accurate screening in computer-aided enzyme design.

Project description:The ability to design effective enzymes is one of the most fundamental challenges in biotechnology and in some respects in biochemistry. In fact, such ability would be one of the most convincing manifestations of a full understanding of the origin of enzyme catalysis. In this work, we explore the reliability of different simulation approaches, in terms of their ability to rank different possible active site constructs. This validation is done by comparing the ability of different approaches to evaluate the catalytic contributions of various residues in chorismate mutase. It is demonstrated that the empirical valence bond (EVB) model can serve as a practical yet accurate tool in the final stages of computer-aided enzyme design (CAED). Other approaches for fast screening are also examined and found to be less accurate and mainly useful for qualitative screening of ionized residues. It is pointed out that accurate ranking of different options for enzyme design cannot be accomplished by approaches that cannot capture the electrostatic preorganization effect. This is in particular true with regard to current design approaches that use gas phase or small cluster calculations and then estimate the interaction between the enzyme and the transition state (TS) model rather than the TS binding free energy or the relevant activation free energy. The ability of the EVB model to provide a tool for quantitative ranking in the final stage of CAED may help in progressing toward the design of enzymes whose catalytic power is closer to that of native enzymes than to that of the current generation of designer enzymes.

| S-EPMC2832760 | biostudies-literature

Computer-aided Drug Design Applied to Parkinson Targets.

Project description:BackgroundParkinson's disease (PD) is a progressive neurodegenerative disorder characterized by debilitating motor deficits, as well as autonomic problems, cognitive declines, changes in affect and sleep disturbances. Although the scientific community has performed great efforts in the study of PD, and from the most diverse points of view, the disease remains incurable. The exact mechanism underlying its progression is unclear, but oxidative stress, mitochondrial dysfunction and inflammation are thought to play major roles in the etiology.ObjectiveCurrent pharmacological therapies for the treatment of Parkinson's disease are mostly inadequate, and new therapeutic agents are much needed.MethodsIn this review, recent advances in computer-aided drug design for the rational design of new compounds against Parkinson disease; using methods such as Quantitative Structure-Activity Relationships (QSAR), molecular docking, molecular dynamics and pharmacophore modeling are discussed.ResultsIn this review, four targets were selected: the enzyme monoamine oxidase, dopamine agonists, acetylcholine receptors, and adenosine receptors.ConclusionComputer aided-drug design enables the creation of theoretical models that can be used in a large database to virtually screen for and identify novel candidate molecules.

| S-EPMC6080092 | biostudies-literature

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