In this study, structural topology scale (ST-scale) was recruited as a novel structural topological descriptor derived from principal component analysis on 827 structural variables of 167 amino acids. By using partial least squares (PLS), we applied ST-scale for the study of quantitative sequence-activity models (QSAMs) on three peptide datasets (58 angiotensin-converting enzyme (ACE) inhibitors, 34 antimicrobial peptides (AMPs) and 89 elastase substrates (ES)). The results of QSAMs were superior to that of the earlier studies, with determination coefficient (r(2)) and cross-validated (q(2)) equal to 0.855, 0.774; 0.79, 0.371 (OSC-PLS: 0.995, 0.848) and 0.846, 0.747, respectively. Therefore, ST-scale descriptors were considered to be competent to extract information from 827 structural variables and relate with their bioactivities.
Compared with the ripenesso fo lefin metathesis, exploration of the construction of carbon-carbon double bonds through the catalytic carbonyl-olefin metathesis reactionr emainss tagnant and has received scant attention. Herein, ah ighlye fficient AuCl 3 -catalyzed intramolecular ring-closing carbonyl-olefin metathesis reaction is described. This method features easily accessible starting materials, simple operation,good functional-group tolerance and short reaction times, and providest he target cyclopentenes, polycycles, benzocarbocycles, and N-heterocycle derivatives in good to excellent yields.Carbon-carbon double-bond formation is one of the useful and fundamentalr eactions in synthetic organic chemistry,p articularly in the synthesis of complex natural products, bioactive molecules, synthetic drugs, and functional organic materials. [1] Generally,c onventional wisdom states that the construction of the carbon-carbond ouble bond mostly relies on the olefination of carbonyl compounds ando lefin metathesis. Since the pioneering work by Wittig, Horner,a nd Emmons,t he synthesis of alkenes by the olefination of carbonyl compounds has evolveda so ne of the most efficient methods, whichu ses phosphorus, sulfur,a nd silicon ylides as highly polarizedn ucleophilic components to add to carbonyl derivatives. [2] Olefin metathesis is another more important approach to obtain olefins andh as brought about ah uge development of many applicationsi ns ynthetic organic chemistry,s ince the discovery of second-generationc atalysts consisting of well-defined metalcarbene complexes, which are mostly based on stable molybdenum or ruthenium. [3] Compared with the ripenesso fo lefin metathesis and Horner-Wadsworth-Emmons reactions, other double-bond metathesis reactions are much less developed, [4] but these metathesis reactions should hold great potential for complex molecular synthesis through one-step synthetict ransformation.Amongt hem, the hitherto elusive carbonyl-olefin metathesis may be the mostp owerful alternative to have appeared in some applications for the total synthesis of naturalp roducts and construction of complex molecules, as usually these molecules are difficult to synthesis by other methods. [5] However, the historical early reports based on photoinduced, stoichiometrica mounts of transition-metal-promotedand even metalalkylidene-mediated carbonyl-olefin metathesish ampered the practicality because of limitations for substrates bearing chromophores, harsh reaction conditions, competing polymerization,h igh cost, and environmental pollution. [6] The fundamental cause of the stagnancy aboutc arbonyl-olefin metathesis lies in:1 )the difficulties in establishing ac atalytic version due to the formation of ak inetically inert metal-oxo complex duringt he cycloreversion step;2 )potential side reactions such as polymerization, ene reaction, alkylation, and Prins reaction etc.;3)regenerationofs tartingc arbonyl-olefinpairs.Recently,t he real breakthrough has begun to dawn because of strategies and catalysts, such...
In this paper, a new set of descriptors, Hydrophobic, Electronic, Steric, and Hydrogen (HESH) (principal components scores vectors of the HESH bond contribution properties), were derived from Principal Component Analysis (PCA) on the collected 171 physicochemical properties of 20 coded amino acids. By applying HESH descriptors to Quantitative Structure -Activity Relationship (QSAR) study on three peptides including 58 Angiotensin-Converting Enzyme (ACE) inhibitors, 48 bitter-tasting dipeptides, and 20 thromboplastin inhibitors, we get three excellent Partial Least Squares (PLS) models, with the squared multiple correlation coefficients (R 2 cum ), cross-validation (R 2 cum ), and Root Mean Square Error (RMSE) of 0.877, 0.838, and 0.361 for ACE inhibitors, 0.926,0.865, and 0.172 for bitter-tasting dipeptides and 0.996, 0.865, and 0.115 for thromboplastin inhibitors. These results were superior to many other reported researches. It showed that HESH may be a useful structural expression method for the study on QSAR of peptide.
P-glycoprotein (P-gp) is an ATP-binding cassette multidrug transporter. The over expression of P-gp leads to the development of multidrug resistance (MDR), which is a major obstacle to effective treatment of cancer. Thus, designing effective P-gp inhibitors has an extremely important role in the overcoming MDR. In this paper, both ligand-based quantitative structure-activity relationship (QSAR) and receptor-based molecular docking are used to predict P-gp inhibitors. The results show that each method achieves good prediction performance. According to the results of tenfold cross-validation, an optimal linear SVM model with only three descriptors is established on 857 training samples, of which the overall accuracy (Acc), sensitivity, specificity, and Matthews correlation coefficient are 0.840, 0.873, 0.813, and 0.683, respectively. The SVM model is further validated by 418 test samples with the overall Acc of 0.868. Based on a homology model of human P-gp established, Surflex-dock is also performed to give binding free energy-based evaluations with the overall accuracies of 0.823 for the test set. Furthermore, a consensus evaluation is also performed by using these two methods. Both QSAR and molecular docking studies indicate that molecular volume, hydrophobicity and aromaticity are three dominant factors influencing the inhibitory activities.
Abstract:The mitochondrial cytochrome P450 enzymes inhibitor steroid 11β-hydroxylase (CYP11B1) can decrease the production of cortisol. Therefore, these inhibitors have an effect in the treatment of Cushing's syndrome. A pharmacophore model generated by Genetic Algorithm with Linear Assignment for Hypermolecular Alignment of Datasets (GALAHAD) was used to align the compounds and perform comparative molecular field analysis (CoMFA) with Q 2 = 0.658, R 2 = 0.959. The pharmacophore model contained six hydrophobic regions and one acceptor atom, and electropositive and bulky substituents would be tolerated at the A and B sites, respectively. A three-dimensional quantitative structure-activity relationship (3D-QSAR) study based on the alignment with the atom root mean square (RMS) was applied using comparative molecular field analysis (CoMFA) with Q 2 = 0.666, R 2 = 0.978, and comparative molecular similarity indices analysis (CoMSIA) with Q 2 = 0.721, R 2 = 0.972. These results proved that all the models have good predictability of the bioactivities of inhibitors. Furthermore, the QSAR models indicated that a hydrogen bond acceptor substituent would be disfavored at the A and B groups, OPEN ACCESSMolecules 2015, 20 1015 while hydrophobic groups would be favored at the B site. The three-dimensional (3D) model of the CYP11B1 was generated based on the crystal structure of the CYP11B2 (PDB code 4DVQ). In order to probe the ligand-binding modes, Surflex-dock was employed to dock CYP11B1 inhibitory compounds into the active site of the receptor. The docking result showed that the imidazolidine ring of CYP11B1 inhibitors form H bonds with the amino group of residue Arg155 and Arg519, which suggested that an electronegative substituent at these positions could enhance the activities of compounds. All the models generated by GALAHAD QSAR and Docking methods provide guidance about how to design novel and potential drugs for Cushing's syndrome treatment.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.