Dock-able linear and homodetic di,tri,tetra and pentapeptide library from canonical amino acids:SARS-CoV-2 Mpro as a case study / 药物分析学报

Peptide-based therapeutics are increasingly pushing to the forefront of biomedicine with their promise of high specificity and low toxicity.Although noncanonical residues can always be used,employing only the natural 20 residues restricts the chemical space to a finite dimension allowing for comprehensive in silico screening.Towards this goal,the dataset comprising all possible di-,tri-,and tetra-peptide com-binations of the canonical residues has been previously reported.However,with increasing computa-tional power,the comprehensive set of pentapeptides is now also feasible for screening as the comprehensive set of cyclic peptides comprising four or five residues.Here,we provide both the com-plete and prefiltered libraries of all di-,tri-,tetra-,and penta-peptide sequences from 20 canonical amino acids and their homodetic(N-to-C-terminal)cyclic homologues.The FASTA,simplified molecular-input line-entry system(SMILES),and structure-data file(SDF)-three dimension(3D)libraries can be readily used for screening against protein targets.We also provide a simple method and tool for conducting identity-based filtering.Access to this dataset will accelerate small peptide screening workflows and encourage their use in drug discovery campaigns.As a case study,the developed library was screened against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)main protease to identify po-tential small peptide inhibitors.

Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches / 药物分析学报

The papain-like protease (PLpro) is vital for the replication of coronaviruses (CoVs), as well as for escaping innate-immune responses of the host. Hence, it has emerged as an attractive antiviral drug-target. In this study, computational approaches were employed, mainly the structure-based virtual screening coupled with all-atom molecular dynamics (MD) simulations to computationally identify specific inhibitors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PLpro, which can be further developed as potential pan-PLpro based broad-spectrum antiviral drugs. The sequence, structure, and functional con-serveness of most deadly human CoVs PLpro were explored, and it was revealed that functionally important catalytic triad residues are well conserved among SARS-CoV, SARS-CoV-2, and middle east respiratory syndrome coronavirus (MERS-CoV). The subsequent screening of a focused protease in-hibitors database composed of ～7,000 compounds resulted in the identification of three candidate compounds, ADM_13083841, LMG_15521745, and SYN_15517940. These three compounds established conserved interactions which were further explored through MD simulations, free energy calculations, and residual energy contribution estimated by MM-PB(GB)SA method. All these compounds showed stable conformation and interacted well with the active residues of SARS-CoV-2 PLpro, and showed consistent interaction profile with SARS-CoV PLpro and MERS-CoV PLpro as well. Conclusively, the re-ported SARS-CoV-2 PLpro specific compounds could serve as seeds for developing potent pan-PLpro based broad-spectrum antiviral drugs against deadly human coronaviruses. Moreover, the presented infor-mation related to binding site residual energy contribution could lead to further optimization of these compounds.

Structural elucidation of SARS-CoV-2 vital proteins: Computational methods reveal potential drug candidates against main protease, Nsp12 polymerase and Nsp13 helicase / 药物分析学报

Recently emerged SARS-CoV-2 caused a major outbreak of coronavirus disease 2019 (COVID-19) and instigated a widespread fear, threatening global health safety. To date, no licensed antiviral drugs or vaccines are available against COVID-19 although several clinical trials are under way to test possible therapies. During this urgent situation, computational drug discovery methods provide an alternative to tiresome high-throughput screening, particularly in the hit-to-lead-optimization stage. Identification of small molecules that specifically target viral replication apparatus has indicated the highest potential towards antiviral drug discovery. In this work, we present potential compounds that specifically target SARS-CoV-2 vital proteins, including the main protease, Nsp12 RNA polymerase and Nsp13 helicase. An integrative virtual screening and molecular dynamics simulations approach has facilitated the identifi-cation of potential binding modes and favourable molecular interaction profile of corresponding com-pounds. Moreover, the identification of structurally important binding site residues in conserved motifs located inside the active site highlights relative importance of ligand binding based on residual energy decomposition analysis. Although the current study lacks experimental validation, the structural infor-mation obtained from this computational study has paved way for the design of targeted inhibitors to combat COVID-19 outbreak.

Qualitative and semi-quantitative analysis of health-care pharmaceutical products using laser-induced breakdown spectroscopy / 药物分析学报

Laser-induced breakdown spectroscopy (LIBS) is a sensitive optical technique that is capable of rapid multi-elemental analysis. The development of this technique for elemental analysis of pharmaceutical products may eventually revolutionize the field of human health. Under normal circumstances, the elemental analysis of pharmaceutical products based on chemical methods is time-consuming and complicated. In this investigation, the principal aim is to develop an LIBS-based methodology for ele-mental analysis of pharmaceutical products. This LIBS technique was utilized for qualitative as well as quantitative analysis of the elements present in Ca-based tablets. All the elements present in the tablets were detected and their percentage compositions were verified in a single shot, using the proposed instrument. These elements (e.g., Ca, Mg, Fe, Zn, and others) were identified by the wavelengths of their spectral lines, which were verified using the NIST database. The approximate amount of each element was determined based on their observed peaks and the result was in exact agreement with the content specification. The determination of the composition of prescription drug for patients is highly important in numerous circumstances. For example, the exploitation of LIBS may facilitate elemental decomposition of medicines to determine the accuracy of the stated composition information. Moreover, the approach can provide element-specific, meaningful, and accurate information related to pharmaceutical products.

Effect of iguratimod on diclofenac metabolism by CYP2C9 in rats and human recombinant CYP2C9 yeast cells

Iguratimod (IGU, also known as T-614), a novel disease modifying antirheumatic drug intended to cure patients with rheumatoid arthritis (RA). The purpose of this study is to evaluate the effect of IGU on the pharmacokinetics of CYP2C9 probe drug diclofenac and its metabolite 4′-hydroxy diclofenac in vivo and in vitro. In in vivo experiments, 24 rats were randomly assigned to three groups consisting of the control group (Normal saline), low dose IGU group (10 mg/kg) and high dose IGU group (30 mg/kg). Blood samples were collected from orbital sinuses vein before 1 hour and serial times of giving diclofenac (15 mg/kg) to all the rats. Plasma concentration of diclofenac and its metabolite 4´-hydroxy diclofenac were assayed by high performance liquid chromatography. Pharmacokinetic parameters were assessed by Winnonlin 6.4 pharmacokinetic software. Moreover, in vitro studies were performed in recombinant human CYP2C9 yeast cell system. IGU at low dose showed no significant differences in the pharmacokinetic parameters of diclofenac and 4-hydroxy diclofenac in vivo when compared with control group (p>0.005). However, at the high dose of IGU, the pharmacokinetic parameters of 4´-hydroxy metabolite of diclofenac increase in half-life (T1/2) and mean area under the curve (AUC0→24), while a decrease in mean clearance (CL, mL/h/kg) and volume of distribution Vz (mL/kg). In addition, in in vitro study, high doses of IGU reduces the metabolism rate of diclofenac. IGU at high dose significantly increase the pharmacokinetics parameters of 4´-hydroxy diclofenac in rats. Additionally, it also showed the potent inhibitory effect on diclofenac metabolism in recombinant human CYP2C9 yeast cells.

The 7th Costal Cartilage Graft for Correcting Saddle Nose Deformity / 昆明医科大学学报

Objective To evaluate the safety and efficacy of the 7th costal cartilage graft for correcting saddle nose deformity.Methods A total of thirty-two patients,10 male and 22 female,were treated from January 2013 to December 2016.The age of the patients ranged from twelve to thirty years with an average of twenty-five years.Fourteen of the thirty-two patients were cases of post traumatic saddle nose deformity,ten were congenital saddle nose deformity,and eight were secondary cleft lip saddle nose deformity.In all of the cases,the 7th costal cartilage was used as an autologous graft for rhinoplasty.The reliability of this method was assessed in term of efficacy and safety including suitability of the graft material,donor site scarring and postoperative results and complications.Results The mean time for harvesting the cartilage was 30 minutes,and the mean length of the harvested 7th costal cartilage was four cm.Postoperatively,there were three cases of nasal deviation,one case of infection and one case where the K-wire exposed.Two patient's hypertrophic scaring on the donor site.All the other cases had positive successful outcomes.Conclusions An autologus 7th costal cartilage can be harvested safely and quickly,and its handling procedure is simple.It is a good option as an autologous graft for rhinoplasty.

Post-Auricular Skin Expansion for Microtia Reconstruction / 昆明医科大学学报

Objective To evaluate the effect of retroauricular skin expansion forthe purpose of ear reconstruction.Methods In this technique called three-stage method:1st soft tissue expander implantation under the skin close to the microtic ear,2nd the autogenous rib cartilage is harvested,the ear framework is prepared and covered with expanded skin.3rd the pseudomeatus,tragus and lobule are formed.Results 50 patients out of 55 patients were satisfied with their result and patients were followed up from 6 months to 2 years and no complain were received,There were few case with minor complication of (Exposure of expander,Deflation or Infection,Exposure of framework,Steel wire extrusion,Hypertrophic scar,Chest wall deformities) and the complications were treated accurately and carefully and patients were discharged after recoveries.Conclusion The three-stage method is very useful in microtia by using costal autogenous rib cartilage.