A Computational Methodology to Overcome the Challenges Associated With the Search for Specific Enzyme Targets to Develop Drugs Against Leishmania major.
Ontology highlight
ABSTRACT:
SUBMITTER: Catharina L
PROVIDER: S-EPMC5470852 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The exploration of biologically relevant chemical space for the discovery of small bioactive molecules present in marine organisms has led not only to important advances in certain therapeutic areas, but also to a better understanding of many life processes. The still largely untapped reservoir of countless metabolites that play biological roles in marine invertebrates and microorganisms opens new avenues and poses new challenges for research. Computational technologies provide the means to (i) organize chemical and biological information in easily searchable and hyperlinked databases and knowledgebases; (ii) carry out cheminformatic analyses on natural products; (iii) mine microbial genomes for known and cryptic biosynthetic pathways; (iv) explore global networks that connect active compounds to their targets (often including enzymes); (v) solve structures of ligands, targets, and their respective complexes using X-ray crystallography and NMR techniques, thus enabling virtual screening and structure-based drug design; and (vi) build molecular models to simulate ligand binding and understand mechanisms of action in atomic detail. Marine natural products are viewed today not only as potential drugs, but also as an invaluable source of chemical inspiration for the development of novel chemotypes to be used in chemical biology and medicinal chemistry research.
| S-EPMC9961086 | biostudies-literature
Project description:We present a fast computational method to efficiently screen enzyme activity. In the presented method, the effect of mutations on the barrier height of an enzyme-catalysed reaction can be computed within 24 hours on roughly 10 processors. The methodology is based on the PM6 and MOZYME methods as implemented in MOPAC2009, and is tested on the first step of the amide hydrolysis reaction catalyzed by the Candida Antarctica lipase B (CalB) enzyme. The barrier heights are estimated using adiabatic mapping and shown to give barrier heights to within 3 kcal/mol of B3LYP/6-31G(d)//RHF/3-21G results for a small model system. Relatively strict convergence criteria (0.5 kcal/(molÅ)), long NDDO cutoff distances within the MOZYME method (15 Å) and single point evaluations using conventional PM6 are needed for reliable results. The generation of mutant structures and subsequent setup of the semiempirical calculations are automated so that the effect on barrier heights can be estimated for hundreds of mutants in a matter of weeks using high performance computing.
| S-EPMC3524253 | biostudies-literature
Project description:One of the main limitations encountered during the chemical synthesis of proteins through native chemical ligation (NCL) is the limited solubility of some of the peptide segments. The most commonly used solution to overcome this problem is to derivatize the segment with a temporary solubilizing tag. Conveniently, the tag can be introduced on the thioester segment in such a way that it is removed concomitantly with the NCL reaction. We herein describe a generalization of this approach to N-terminal cysteinyl segment counterparts, using a straightforward synthetic approach that can be easily automated from commercially available building blocks, and applied it to a well-known problematic target, SUMO-2.
| S-EPMC8179351 | biostudies-literature
Project description:Enzymes are powerful biocatalysts, however, so far there is still a large gap between the number of enzyme-based practical applications and that of naturally occurring enzymes. Multiple experimental approaches have been applied to generate nearly all possible mutations of target enzymes, allowing the identification of desirable variants with improved properties to meet the practical needs. Meanwhile, an increasing number of computational methods have been developed to assist in the modification of enzymes during the past few decades. With the development of bioinformatic algorithms, computational approaches are now able to provide more precise guidance for enzyme engineering and make it more efficient and less laborious. In this review, we summarize the recent advances of method development with significant biological outcomes to provide important insights into successful computational protein designs. We also discuss the limitations and challenges of existing methods and the future directions that should improve them.
| S-EPMC3962085 | biostudies-literature
Project description:In this study, we used in silico techniques to identify available parasite treatments, representing a promising therapeutic avenue. Building upon our computational initiatives aimed at discovering natural inhibitors for various target enzymes from parasites causing neglected tropical diseases (NTDs), we present novel findings on three turmeric-derived phytochemicals as inhibitors of Leishmania pteridine reductase I (PTR1) through in silico methodologies. PTR1, a crucial enzyme in the unique folate metabolism of trypanosomatid parasites, holds established therapeutic significance. Employing MOE software, a molecular docking analysis assesses the efficacy of turmeric phytochemicals against Leishmania PTR1. Validation of the docking protocol is confirmed with an RMSD value of 2. Post-docking, compounds displaying notable interactions with critical residues and binding affinities ranging between -6 and -8 kcal/mol are selected for interaction pattern exploration. Testing twelve turmeric phytochemicals, including curcumin, zingiberene, curcumol, curcumenol, eugenol, bisdemethoxycurcumin, tetrahydrocurcumin, tryethylcurcumin, turmerones, turmerin, demethoxycurcumin, and turmeronols, revealed binding affinities ranging from -5.5 to -8 kcal/mol. Notably, curcumin, demethoxycurcumin, and bisdemethoxycurcumin exhibit binding affinities within -6.5 to -8 kcal/mol and establish substantial interactions with catalytic residues. These phytochemicals hold promise as lead structures for rational drug design targeting Leishmania spp. PTR in future applications. This work underscores the potential of these identified phytochemicals in the development of more effective inhibitors, demonstrating their relevance in addressing neglected tropical diseases caused by parasites.
| S-EPMC10963314 | biostudies-literature
Project description:A great number of sesquiterpenes are reported in the available literature as good antileishmanial leads. However, their mode of action at the molecular level has not been elucidated. The lack of molecular studies could be considered an impediment for studies seeking to improve sesquiterpene-based drug design. The present in silico study allows us to make important observations about the molecular details of the binding modes of a set of antileishmanial sesquiterpenes against four drug-enzyme targets [pteridine reductase-1 (PTR1), N-myristoyl transferase (NMT), cysteine synthase (CS), trypanothione synthetase (TryS)]. Through molecular docking it was found that two sesquiterpene coumarins are promising leads for the PTR1 and TryS inhibition purposes, and some xanthanolides also exhibited better affinity towards PTR1 and CS binding. In addition, the affinity values were clustered by Principal Component Analysis and drug-like properties were analyzed for the strongest-docking sesquiterpenes. The results are an excellent starting point for future studies of structural optimization of this kind of compounds.
| S-EPMC6271876 | biostudies-literature
Project description:RNA-based therapies, including RNA molecules as drugs and RNA-targeted small molecules, offer unique opportunities to expand the range of therapeutic targets. Various forms of RNAs may be used to selectively act on proteins, transcripts, and genes that cannot be targeted by conventional small molecules or proteins. Although development of RNA drugs faces unparalleled challenges, many strategies have been developed to improve RNA metabolic stability and intracellular delivery. A number of RNA drugs have been approved for medical use, including aptamers (e.g., pegaptanib) that mechanistically act on protein target and small interfering RNAs (e.g., patisiran and givosiran) and antisense oligonucleotides (e.g., inotersen and golodirsen) that directly interfere with RNA targets. Furthermore, guide RNAs are essential components of novel gene editing modalities, and mRNA therapeutics are under development for protein replacement therapy or vaccination, including those against unprecedented severe acute respiratory syndrome coronavirus pandemic. Moreover, functional RNAs or RNA motifs are highly structured to form binding pockets or clefts that are accessible by small molecules. Many natural, semisynthetic, or synthetic antibiotics (e.g., aminoglycosides, tetracyclines, macrolides, oxazolidinones, and phenicols) can directly bind to ribosomal RNAs to achieve the inhibition of bacterial infections. Therefore, there is growing interest in developing RNA-targeted small-molecule drugs amenable to oral administration, and some (e.g., risdiplam and branaplam) have entered clinical trials. Here, we review the pharmacology of novel RNA drugs and RNA-targeted small-molecule medications, with a focus on recent progresses and strategies. Challenges in the development of novel druggable RNA entities and identification of viable RNA targets and selective small-molecule binders are discussed. SIGNIFICANCE STATEMENT: With the understanding of RNA functions and critical roles in diseases, as well as the development of RNA-related technologies, there is growing interest in developing novel RNA-based therapeutics. This comprehensive review presents pharmacology of both RNA drugs and RNA-targeted small-molecule medications, focusing on novel mechanisms of action, the most recent progress, and existing challenges.
| S-EPMC7495341 | biostudies-literature
Project description:Histone acetyltransferase (HAT) is an enzyme required for chromatin remodeling and transcriptional activation. Sarcoendoplasmic reticulum Ca(2+) ATPase (SERCA) is an ATP coupled Ca(2+) ion pump involved in metabolic arrest. Both these enzymes are present in Plasmodia and have been selected as molecular targets for in silico studies of some new non-resistant antimalarial drugs like artemisinin, curcumin and diarylheptanoids along with some other inhibitors reported in literature. Ten top inhibitors have also been generated based on common pharmacophore from ZINC database. The HAT enzyme was modeled with the help of the Modeller software and the SERCA enzyme pdb file was obtained from the protein data bank. Ligbuilder was used for structure based drug designing, which generated a common pharmacophore of the ligands. Molegro was used to perform virtual screening of the hits from the pharmacophore based Zinc database search and known inhibitors of the enzymes from the literature survey. Curcumin shows good and optimal binding to both HAT and SERCA enzymes; therefore it might be a good inhibitor of these key enzymes in Plasmodium. Curcumin is reported to act synergistically with artemisinin which forms covalent adducts with the transmembrane proteins (SERCA enzyme) and inactivates them, thus inhibiting the activity of Plasmodium parasite. This combination has already been reported to be effective in malaria treatment. Some other diarylheptanoids besides curcumin showed better binding to both the enzymes. Therefore, a combination of artemisinin and diarylheptanoids can prove to be better combination for antimalarial therapy. Different formulations involving curcumin, artimisinin and diarylheptanoids may result in a more potent antimalarial drug.
| S-EPMC2646860 | biostudies-other
Project description:BackgroundThe development of new therapeutic strategies to treat patients for leishmaniasis has become a priority. The antileishmanial activity of the strychnobiflavone flavonoid was recently demonstrated against Leishmania amazonensis and Leishmania infantum amastigotes and promastigotes. The biological effect of this molecule was identified due to its capacity to interfere in the parasite mitochondrial membrane; however, the underlying molecular mechanism remains unclear.Methods and resultsIn this study, a computational approach using bioinformatics was performed to screen biological targets of strychnobiflavone in L. infantum. Computational programs, such as the target fishing approach and molecular docking assays, were used. Results showed that the putative pathway targeted by strychnobiflavone in L. infantum is the methylglyoxal degradation superpathway, and one hydrolase-like protein was predicted to be the molecular target of this flavonoid in the parasites.ConclusionIn this context, this study provides the basis for understanding the mechanism of action of strychnobiflavone in L. infantum and presents a strategy based on bioinformatics programs to screen targets of other molecules with biological action against distinct pathogens.
| S-EPMC5896251 | biostudies-literature
Project description:The aim of this study was to utilize a computational methodology based on Gene Reversal Rate (GRR) scoring to repurpose existing drugs for a rare and understudied cancer: inflammatory breast cancer (IBC). This method uses IBC-related gene expression signatures (GES) and drug-induced gene expression profiles from the LINCS database to calculate a GRR score for each candidate drug, and is based on the idea that a compound that can counteract gene expression changes of a disease may have potential therapeutic applications for that disease. Genes related to IBC with associated differential expression data (265 up-regulated and 122 down-regulated) were collated from PubMed-indexed publications. Drug-induced gene expression profiles were downloaded from the LINCS database and candidate drugs to treat IBC were predicted using their GRR scores. Thirty-two (32) drug perturbations that could potentially reverse the pre-compiled list of 297 IBC genes were obtained using the LINCS Canvas Browser (LCB) analysis. Binary combinations of the 32 perturbations were assessed computationally to identify combined perturbations with the highest GRR scores, and resulted in 131 combinations with GRR greater than 80%, that reverse up to 264 of the 297 genes in the IBC-GES. The top 35 combinations involve 20 unique individual drug perturbations, and 19 potential drug candidates. A comprehensive literature search confirmed 17 of the 19 known drugs as having either anti-cancer or anti-inflammatory activities. AZD-7545, BMS-754807, and nimesulide target known IBC relevant genes: PDK, Met, and COX, respectively. AG-14361, butalbital, and clobenpropit are known to be functionally relevant in DNA damage, cell cycle, and apoptosis, respectively. These findings support the use of the GRR approach to identify drug candidates and potential combination therapies that could be used to treat rare diseases such as IBC.
| S-EPMC10576937 | biostudies-literature