Refinement of Catalyst hypotheses using simplex optimisation

The program HypoOpt in combination with the MSI program citest has been used to optimise and expand 3D QSAR Catalyst hypotheses using simplex optimisation coupled with cross-validation. Three data sets related to angiotensin converting enzyme inhibition, squalene epoxidase inhibition and HIV protease inhibition were used to investigate the outcome of hypothesis optimisation. Simplex optimisation using leave-one-out cross-validation during the hypothesis refinement resulted in improved models with respect to predictivity of an external test set. Furthermore, the utilisation of the geometry of the active site for the HIV protease inhibitors, represented by Catalyst `excluded volume' features, resulted in an optimised hypothesis with improved predictivity compared with the corresponding hypothesis derived without receptor information.     

The Two-Way Switch Role of ACE2 in the Treatment of Novel Coronavirus Pneumonia and Underlying Comorbidities

December 2019 saw the emergence of the coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which has spread across the globe. The high infectivity and ongoing mortality of SARS-CoV-2 emphasize the demand of drug discovery. Angiotensin-converting enzyme II (ACE2) is the functional receptor for SARS-CoV-2 entry into host cells. ACE2 exists as a membrane-bound protein on major viral target pulmonary epithelial cells, and its peptidase domain (PD) interacts SARS-CoV-2 spike protein with higher affinity. Therefore, targeting ACE2 is an important pharmacological intervention for a SARS-CoV-2 infection. In this review, we described the two-way switch role of ACE2 in the treatment of novel coronavirus pneumonia and underlying comorbidities, and discussed the potential effect of the ACE inhibitor and angiotensin receptor blocker on a hypertension patient with the SARS-CoV-2 infection. In addition, we analyzed the S-protein-binding site on ACE2 and suggested that blocking hot spot-31 and hot spot-353 on ACE2 could be a therapeutic strategy for preventing the spread of SARS-CoV-2. Besides, the recombinant ACE2 protein could be another potential treatment option for SARS-CoV-2 induced acute severe lung failure. This review could provide beneficial information for the development of anti-SARS-CoV-2 agents via targeting ACE2 and the clinical usage of renin-angiotensin system (RAS) drugs for novel coronavirus pneumonia treatment.     

In Silico Studies of Some Isoflavonoids as Potential Candidates against COVID-19 Targeting Human ACE2 (hACE2) and Viral Main Protease (Mpro)

The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the “COVID-19” disease that has been declared by WHO as a global emergency. The pandemic, which emerged in China and widespread all over the world, has no specific treatment till now. The reported antiviral activities of isoflavonoids encouraged us to find out its in silico anti-SARS-CoV-2 activity. In this work, molecular docking studies were carried out to investigate the interaction of fifty-nine isoflavonoids against hACE2 and viral M^pro. Several other in silico studies including physicochemical properties, ADMET and toxicity have been preceded. The results revealed that the examined isoflavonoids bound perfectly the hACE-2 with free binding energies ranging from −24.02 to −39.33 kcal mol⁻¹, compared to the co-crystallized ligand (−21.39 kcal mol^–1). Furthermore, such compounds bound the M^pro with unique binding modes showing free binding energies ranging from −32.19 to −50.79 kcal mol^–1, comparing to the co-crystallized ligand (binding energy = −62.84 kcal mol^–1). Compounds 33 and 56 showed the most acceptable affinities against hACE2. Compounds 30 and 53 showed the best docking results against M^pro. In silico ADMET studies suggest that most compounds possess drug-likeness properties.     

Genetic analysis of SARS-CoV-2 isolates collected from Bangladesh: Insights into the origin,mutational spectrum and possible pathomechanism

As the coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), rages across the world, killing hundreds of thousands and infecting millions, researchers are racing against time to elucidate the viral genome. Some Bangladeshi institutes are also in this race, sequenced a few isolates of the virus collected from Bangladesh. Here, we present a genomic analysis of these isolates. The analysis revealed that SARS-CoV-2 isolates sequenced from Dhaka and Chittagong were the lineage of Europe and India, respectively. Our analysis identified a total of 42 mutations, including three large deletions, half of which were synonymous. Most of the missense mutations in Bangladeshi isolates found to have weak effects on the pathogenesis. Some mutations may lead the virus to be less pathogenic than the other countries. Molecular docking analysis to evaluate the effect of the mutations on the interaction between the viral spike proteins and the human ACE2 receptor, though no significant difference was observed. This study provides some preliminary insights into the origin of Bangladeshi SARS-CoV-2 isolates, mutation spectrum and its possible pathomechanism, which may give an essential clue for designing therapeutics and management of COVID-19 in Bangladesh.     

Effects of ultrasound pretreatment with different frequencies and working modes on the enzymolysis and the structure characterization of rice protein

The effects of ultrasound pretreatment with different frequencies and working modes, including mono-frequency ultrasound (MFU), dual-frequency ultrasound (DFU) and tri-frequency ultrasound (TFU), on the degree of hydrolysis (DH) of rice protein (RP) and angiotensin-I-converting enzyme (ACE) inhibitory activity of RP hydrolysate were investigated. Ultraviolet–visible (UV) spectroscopy, fourier transform infrared (FTIR) spectroscopy, surface hydrophobicity and scanning electron microscopy (SEM) of RP pretreated with ultrasound were measured. The results showed that ultrasound pretreatment did not increase DH of RP significantly (p > 0.05). However, all the ultrasound pretreatment increased the ACE inhibitory activity of RP hydrolysate significantly (p < 0.05). The MFU of 20 kHz showed higher ACE inhibitory activity compared to that of other MFU. The ACE inhibitory activity of sequential DFU was higher than that of simultaneous with the same frequency combination. Sequential TFU of 20/35/50 kHz produced the highest increase in ACE inhibitory activity in contrast with other ultrasound frequencies and working modes. All the results under ultrasound pretreatment showed that ultrasound frequencies and working modes were of great effect on the ACE inhibitory activity of RP. The changes in UV–Vis spectra and surface hydrophobicity indicated the unfolding of protein and exposure of hydrophobic groups by ultrasound. The FTIR analysis showed that all the ultrasound pretreatment with different frequencies and working modes decreased α-helix, β-turn content and increased β-sheet, random coil content of RP. The SEM results indicated that ultrasound pretreatment resulted in the deformation of RP. In conclusion, the frequency selection of ultrasound pretreatment of RP is essential for the preparation of ACE inhibitory peptide.     

SYNTHESIS AND APPLICATION AS POLYMER ELECTROLYTE OF HOMO- AND COPOLYMERS OF 3-(2-CYANO ETHOXY)METHYL- AND 3-(METHOXY(TRIETHYLENOXY))METHYL-3′-METHYLOXETANE

 Two oxetane-derived monomers, 3-(2-cyano-ethoxy)methyl- and 3-(methoxy-(triethylenoxy))methyl-3′-methyloxetane (COX and MTOX), were prepared from 3-hydroxymethyl-3-methyloxetane. Their homo- and co-polymerization in solution were carried out by the cationic ring-opening polymerization with BF₃•Et₂O and 1,4-butanediol as co-initiator. The molecular weight and molecular weight distribution were determined using GPC so as to reveal the competition and interchange between active chain end (ACE) and activated monomer (AM) mechanism in the process. The reactivity ratios of the two monomers were calculated according to Kelen-Tudos using ¹H-NMR analysis. The influence of functional side chains in the monomers on the copolymerization behaviors was discussed in virtue of the reactivity ratio data. When doped with lithium salt LiTFSI, the ion conductivity of the homopolymer of MTOX reached 10^-3.58 S/cm at 30℃ and  10^-2.73 S/cm at 80℃, respectively, showing its potential to be used as polymer electrolyte for lithium ion battery.     

基于酪氨酸端基的ACE三肽抑制剂定量构效关系研究

固定酪氨酸为端基对ACE三肽抑制剂进行构效关系研究,采用多元线性回归方法,基于不同描述符建立模型,比较模型的可靠性和准确性.结果表明Z描述子建立的模型最好.定量构效关系研究表明ACE抑制三肽第二位氨基酸的电性参数是抑制活性的最大影响因素.     

Improved multicomponent,one-pot synthesis of functionalized tetrahydropyrans cardiovascular dysfunction regulators

A simple, efficient, and straightforward one-pot three-component synthesis of functionalized tetrahydropyrans ( 6a-l ) is carried-out in the presence of an inexpensive and environmentally benign Eaton's reagent as a catalyst to discover some ACE inhibitors and anti-inflammatory agents. Angiotensin-converting enzyme (ACE) is highly involved in the renin-angiotensin system and often directly associated with cardiovascular dysfunction via inflammation. Thus, the cardiovascular protective effect of newly synthesized tetrahydropyrans ( 6a-l ) was evaluated through ACE inhibition, human red blood cell (HRBC) membrane stabilization, and molecular docking studies. As the results complied, compounds 6e and 6f were identified as effective ACE inhibitors. Docking studies, HRBC based anti-inflammatory assay, and SAR studies revealed that compounds 6e and 6f could be good anti-inflammatory agents apart from ACE inhibitors.