Using Molinspiration as a didactic complement into teaching subjects of Medicinal Chemistry

Medicinal Chemistry has high rates of failure and abandonment at the beginning of the courses where this disciplines are taught, as occurs in pharmaceutical sciences. In University of Algarve (UAlg), there has been an effort to avoid school failure in these topics by increasing student motivation, a very important issue for the students get success. For this has been used in teaching Medicinal Chemistry, the web application called Molinspiration. This website/tool allows one to input a chemical structure and then after, view predicted properties of structure and its bioactivity against six different common drug targets. Using this application, students are transported to a virtual laboratory which making easier to understand and practice the basic scientific knowledge that has been previously explained in theoretical classes.info:eu-repo/semantics/publishedVersio

5-Hydroxy-3-(4-hydroxyphenyl)-8,8-dimethyl-6- (3-methylbut-2-enyl)pyrano[2,3-h]chromen-4-one

Natural and semi-synthetic compounds are being studied as novel phosphodiesterase 5 (PDE5) inhibitors for the treatment of erectile dysfunction, pulmonary hypertension, and lower urinary symptoms. Maclura pomifera is a source of flavonoids, one of the main classes of molecules investigated for these purposes. The extraction of the natural isoflavone osajin and its modification to obtain a semi-synthetic derivative are described in this short note. 1H and 13C-nuclear magnetic resonance spectroscopy (NMR), mass spectrometry, high-performance liquid chromatography (HPLC) and spectroscopic characterization of the title compound are also hereby provided. Two-dimensional (2D) nuclear Overhauser effect spectroscopy (NOESY) NMR, supported by in silico conformational studies, was used to achieve a complete assignment of the proton signals, assessing the correct chemical structure of the compound. Heteronuclear single quantum coherence spectroscopy (HSQC) and heteronuclear multiple bond correlation (HMBC) NMR experiments were performed to assign 13C chemical shifts. Calculated chemical properties and preliminary in silico docking suggest that this molecule might be a promising candidate as PDE5 inhibitor

In silico studies on olive oil polyphenolic natural products to identify neuroprotective lead compounds beneficial in the treatment of Alzheimer's disease

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders. Nearly 44 million people across the globe are living with it. In spite of tremendous progress in understanding the pathophysiology of AD, only a few drugs have been approved by FDA to date that too provides only symptomatic relief. We have contemplated historical and religious backgrounds in addition to the literature review and concluded that polyphenolic natural products from olive oil can be used for the treatment of AD. The current computational study was designed to investigate the potential of phenolic metabolites present in olive oil to identify lead molecule(s) that could help in fighting against AD. A total of 21 phenolic compounds from olive oil were selected, and their SMILES notations were generated using Chemsketch. Cheminformatics software such as, Molinspiration to predict the bioactivity scores and physicochemical properties, PASS to predict the acetylcholinesterase (AChE) inhibition, neuroprotective, antioxidants, and anti-inflammatory activities; OSIRIS for pharmacokinetic profile and toxicity and Autodock Vina for molecular docking were used for in silico studies. The results were compared with four clinically used AD drugs. All the tested compounds were predicted to possess anti-inflammatory activity (0.357-0.831 Pa score) and antioxidant activity (0.320-0.903 Pa values), but none of the compounds was found to be a butyrylcholinesterase inhibitor. Out of 21 initial polyphenolic compounds, we selected the best two bioactive compounds, luteolin and elenolic acid, based on their bioactivity and toxicity profile. Luteolin showed the most stable binding to both beta-secretase- 1 (BACE) and AChE enzymes followed by elenolic acid. It is concluded that luteolin and elenolic acid are the most potent polyphenolic compounds of the olive, which act at multiple targets in AD pathogenesis. These compounds hold promise for the development of anti-Alzheimer's therapy

Pharmacokinetic study with computational tools in the medicinal chemistry course

To improve the teaching-learning process in the Medicinal Chemistry course, new strategies have been incorporated into practical classes of this fundamental discipline of the pharmaceutical curriculum. Many changes and improvements have been made in the area of medicinal chemistry so far, and students should be prepared for these new approaches with the use of technological resources in this field. Practical activities using computational techniques have been directed to the evaluation of chemical and physicochemical properties that affect the pharmacokinetics of drugs. Their objectives were to allow students to know these tools, to learn how to access them, to search for the structures of drugs and to analyze results. To the best of our knowledge, this is the first study in Brazil to demonstrate the use of computational practices in teaching pharmacokinetics. Practical classes using Osiris and Molinspiration were attractive to students, who developed the activities easily and acquired better theoretical knowledge.Para melhorar o processo ensino-aprendizagem no curso de Química Medicinal novas estratégias estão sendo incorporadas às aulas práticas desta disciplina fundamental do currículo farmacêutico. Muitas mudanças e melhorias vêm marcando a área de química medicinal e por isso é importante que os alunos sejam colocados nestas novas abordagens na área, com a utilização de recursos tecnológicos. As atividades práticas foram direcionadas para a avaliação dos dados químicos e físico-químicos de fármacos que influenciam as propriedades farmacocinéticas com o auxílio de técnicas computacionais. Os objetivos foram permitir aos alunos conhecer essas ferramentas, saber como acessá-las, procurar as estruturas de fármacos e analisar os resultados. Este é o primeiro estudo publicado no Brasil que apresenta aula prática computacional sobre o tema farmacocinética. As aulas práticas utilizando os servidores Osiris e Molinspiration foram atraentes para os alunos, que desenvolveram as atividades com maior facilidade e sedimentaram o conhecimento teórico adquirido em sala de aula

IN SILICO EVALUATION OF ANGIOTENSIN II RECEPTOR ANTAGONIST’S PLASMA PROTEIN BINDING USING COMPUTED MOLECULAR DESCRIPTORS

The discovery of new pharmacologically active substances and drugs modeling led to necessity of predicting drugs properties and its ADME data. Angiotensin II receptor antagonists are a group of pharmaceuticals which modulate the renin-angiotensin-aldosterone system and today represent the most commonly prescribed anti-hypertensive drugs. The aim of this study was to compare different molecular properties of seven angiotensin II receptor antagonists / blockers (ARBs), (eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan) and their plasma protein binding (PPB) data. Several ARBs molecular descriptors were calculated using software package Molinspiration Depiction Software as well as Virtual Computational Chemistry Laboratory (electronic descriptor – PSA, constitutional parameter – Mw, geometric descriptor – Vol, lipophilicity descriptors - logP values, aqueous solubility data – logS). The correlations between all collected descriptors and plasma protein binding data obtained from relevant literature were established. In the simple linear regression poor correlations were obtained in relationships between PPB data and all calculated molecular descriptors. In the next stage of the study multiple linear regression (MLR) was used for correlation of PPB data with two different descriptors as independent variables. The best correlation (R2=0.70 with P<0.05) was established between PPB data and molecular weight with addition of volume values as independent variables. The possible application of computed molecular descriptors in drugs protein binding evaluation can be of great importance in drug research

ANTIOXIDANT, ANTIMICROBIAL, ANTIPROLIFERATIVE ACTIVITIES AND IN SILICO DRUG LIKENESS PREDICTION OF PURIFIED MHH COMPOUND, ISOLATED FROM MILLINGTONIA HORTENSIS LINN

Objective: To investigate the antioxidant, antimicrobial, antiproliferative activities and in silico drug likeness prediction of the MHH compound.Methods: The antioxidant, antimicrobial and antiproliferative activities of the MHH compound have been evaluated by 1,1-Diphenyl-2-picryl hydrazyl (DPPH) and Ferric Reducing Antioxidant Power (FRAP) assays, agar well diffusion assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay respectively. The cytotoxicity activity and in silico drug likeness prediction of the MHH compound have been studied.Results: The DPPH radical scavenging activity and the total antioxidant power of the MHH compound were found to be 92.48%±2.06 and 10.698±0.23 mM Fe (II)/g respectively. The antimicrobial activity of MHH compound against Escherichia coli, Klebsiella pneumonia, Proteus vulgaris, Salmonella typhi, Staphylococcus aureus and Streptomyces griseus, Candida albicans, Aspargillus flavus and the zones of inhibition were found to be 16.83 mm, 19.83 mm, 15.23 mm, 16.79 mm, 13.57 mm, 19.65 mm, 18.66 mm and 14.79 mm respectively. The IC50 values of the MHH compound for HeLa and HCT-15 cell lines were found to be 371.92 μg/ml and 112.06 μg/ml respectively. The LC50 value of MHH compound was 218.765µg/ml and 152.78µg/ml which is considered as moderately cytotoxic and toxic respectively when incubated at 24 h and 48 h. The drug likeness and bioactivity scores of the MHH compound were found to be within the range and followed Lipinski's rule.Conclusion: This study concludes that the MHH compound has significant biological activities and can be used as the therapeutic agent.Â

Drug Analogs of COX-2 Selective Inhibitors Lumiracoxib and Valdecoxib Derived from in silico Search and Optimization

The medicinal activity of COX-2 inhibitors are sufficiently beneficial to urge the search for new drug designs. This study presents 16 analogs of lumiracoxib and 10 analogs to valdecoxib having properties suitable as COX-2 inhibitors. For lumiracoxib analogs the mean Log P, polar surface area, and formula weight are 3.00, 70.46 A2, and 276.60, respectively. For valdecoxib analogs the mean Log P, polar surface area, and formula weight are 3.65, 68.46 A2, and 322.32, respectively. Grubb’s test analysis of seven properties for seven known COX-2 selective inhibitors and those of 26 analog compounds indicated no outliers. The unpaired t-test compared Log P and polar surface area of seven known COX-2 inhibitors to all 26 analogs and found no difference. All 26 analogs showed no violation of the Rule of 5, this being an indicator of favorable bioavailability. Hierarchical cluster analysis by single linkage indicated lumiracoxib is most similar to analogs 2, 4, 5, 6, 7, 9, 10, 11, 14, 15, 16, and 17. Valdecoxib has highest similarity to analogs 8, 19, 21, 22, 23, 26, 27, and 28. Multiple regression analysis successfully produced equations for prediction of similar compounds to lumiracoxib and valdecoxib. Path analysis indicated that number of atoms, oxygen & nitrogen atoms, and Log P are the greatest determinants for formula weight for known COX-2 inhibitors. Criteria for molecular properties is established for identifying COX-2 inhibitors. These 26 analogs show much potential for active COX-2 inhibition

IN-SILICO DESIGN, SYNTHESIS AND IN VITRO ANTICANCER AND ANTITUBERCULAR ACTIVITY OF NOVEL AZETIDINONE CONTAINING ISATIN DERIVATIVES

Objective: To design, synthesize and in vitro anticancer and antitubercular evaluation of some new isatin derivatives containing azetidinone. Methods: Novel azetidinone containing isatin derivatives were designed by using various softwares such as ACD Lab ChemSketch 12.0, Marvin Sketch, Molinspiration, PASS and Schrodinger. The designed molecules having required physico-chemical properties, drug likeness and obeying Lipinski's rule of five were selected for the synthesis. These compounds were synthesized by conventional and microwave assisted synthetic methods through a series of three steps. The synthesized compounds were subjected to TLC, melting point determination, IR, 1HNMR and Mass spectroscopic studies. The in vitro anticancer activity of selected compounds was evaluated against MCF7 and L929 by MTT assay method. The antitubercular activity of selected compounds was evaluated by REMA method. Results: Ten derivatives (AZ-2, AZ-3, AZ-5, AZ-8, AZ-9, AZ-10, AZ-12, AZ-13, AZ-14 and AZ-15) were selected for synthesis with the help of in-silico modeling. In the synthesis, the microwave method took minimum reaction time and gave maximum yield comparing with conventional method. All the synthesized compounds showed characteristic peak in IR, 1HNMR and Mass spectroscopic studies. Based on the Schrodinger Glide XP score, the compounds AZ-13, AZ-5 and AZ-3 were selected for in vitro anticancer and AZ-9, AZ-14 and AZ-3 were selected for antitubercular evaluation. The compound AZ-13 showed significant anticancer activity particularly against L929 cell line and the compound AZ-9 showed significant antitubercular activity comparing with other selected compounds. Conclusion: These results are useful for further investigation in the future. Â&nbsp

IN SILICO DESIGN AND MOLECULAR DOCKING STUDIES OF SOME 1, 2-BENZISOXAZOLE DERIVATIVES FOR THEIR ANALGESIC AND ANTI-INFLAMMATORY ACTIVITY

Objective: In silico design and molecular docking of 1,2-benzisoxazole derivatives for their analgesic and anti-inflammatory activity using computational methods.Methods: In silico molecular properties of 1,2-benzisoxazole derivatives were predicted using various software's such as Chemsketch, Molinspiration, PASS and Schrodinger to select compounds having optimum drug-likeness, molecular descriptors resembling those of standard drugs and not violating the ‘Lipinski rule of 5'. Molecular docking was performed on active site of nicotinic acetylcholine receptor (PDB: 2KSR) for analgesic activity and COX-2 (PDB: 6COX) for anti-inflammatory activity using Schrodinger under maestro molecular modelling environment.Results: From the results of molecular docking studies of 1,2-benzisoxazole derivatives, all the compounds showed good binding interactions with Nicotinic acetylcholine receptor and COX-2. Compounds 4a and 4c showed highest binding scores (-7.46 and-7.21 respectively) with nicotinic acetylcholine receptor and exhibited maximum analgesic activity. Compound 4a showed highest binding score (-7.8) with COX-2 and exhibited maximum anti-inflammatory activity.Conclusion: All the derivatives of 1,2-benzisoxazole showed good analgesic and anti-inflammatory activity as predicted using molecular docking on respective receptors