Eyes on Lipinski's Rule of Five: A New “Rule of Thumb” for Physicochemical Design Space of Ophthalmic Drugs

Background: Diabetes affects millions of people worldwide, with predicted numbers of about 700 million adults affected by 2045. Among the several anti-diabetic drug therapies available in the market, Dipeptidyl Peptidase-4 (DPP-4) inhibitors have emerged as a promising therapeutic approach with scope for exploration in the segment of peptidomimetics. Objective: Series of proline-containing peptidomimetic compounds were designed and investigated for their drug-likeness through Lipinski’s rule of five, lead-likeness through the rule of three, predictive pharmacokinetic studies (absorption, distribution, metabolism, and excretion), and toxicity properties through in-silico approaches. The designed compounds were evaluated for their interactions with binding sites of the enzyme DPP-4 using an extra precision docking approach. Methods: Proline-containing peptidomimetic compounds were designed rationally. Drug-likeness and lead-likeness properties were calculated using Schrödinger Maestro v11.2 software. ADME and toxicity properties were predicted using PreADMET version 2.0. Docking study was performed using Schrödinger Maestro v11.2 software, and ligands for the study were designed using MarvinSketch software. Results: 5(S)-methyl-L-proline containing 17 ligands were designed. All of them were found to obey Lipinski’s rule of five. Compounds were found to have good ADME profile and low toxicity predictions. Conclusion: Four compounds were found to have good interactions with DPP-4 binding sites and hence created the scope to develop a DPP-4 inhibitors containing 5(S)-methyl-L-proline moiety.

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Molecular Docking Studies of Flavonoids from Andrographis paniculata as Potential Acetylcholinesterase, Butyrylcholinesterase and Monoamine Oxidase Inhibitors Towards the Treatment of Neurodegenerative Diseases

Biointerface Research in Applied Chemistry ◽

10.33263/briac113.98719879 ◽

2020 ◽

Vol 11 (3) ◽

pp. 9871-9879

Keyword(s):

Molecular Docking ◽

Monoamine Oxidase ◽

Neurodegenerative Diseases ◽

Docking Studies ◽

Monoamine Oxidase Inhibitors ◽

Andrographis Paniculata ◽

Lipinski’S Rule ◽

Bioinformatic Tools ◽

Pubchem Database ◽

Lipinski’S Rule Of Five

Neurodegenerative diseases have been characterized by loss of neuron structures as well as their functions. This study was designed to assess molecular docking of flavonoids from Andrographis paniculata as potential acetylcholinesterase, butyrylcholinesterase, and monoamine oxidase inhibitors in the treatment of neurodegenerative diseases. Eight identified possible inhibitors of acetylcholinesterase, butyrylcholinesterase, and monoamine oxidase from Andrographis paniculata were retrieved from the PubChem database. The molecular docking, ADMET, and Lipinski’s rule of five were examined using different bioinformatic tools. It was shown that only rutin has the highest binding affinity (-12.6 kcal/mol) than the standard used. ADMET results demonstrated that all the eight compounds are druggable candidates except rutin. Also, only tangeritin has a blood-brain barrier (BBB) permeation potential. Hence, it can be deduced that all flavonoid compounds from Andrographis paniculata are orally druggable, which can make them useful in the treatment of neurodegenerative diseases better than donepezil.

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New Spiro[cycloalkane-pyridazinone] Derivatives with Favorable Fsp3 Character

Chemistry ◽

10.3390/chemistry2040055 ◽

2020 ◽

Vol 2 (4) ◽

pp. 837-848

Author(s):

Csilla Sepsey Für ◽

Hedvig Bölcskei

Keyword(s):

High Throughput Screening ◽

Pharmaceutical Companies ◽

Compound Library ◽

Aromatic Rings ◽

Lead Discovery ◽

Lipinski’S Rule ◽

Design And Synthesis ◽

Lipinski’S Rule Of Five ◽

Pyridazinone Derivatives ◽

New Compounds

The large originator pharmaceutical companies need more and more new compounds for their molecule banks, because high throughput screening (HTS) is still a widely used method to find new hits in the course of the lead discovery. In the design and synthesis of a new compound library, important points are in focus nowadays: Lipinski’s rule of five (RO5); the high Fsp3 character; the use of bioisosteric heterocycles instead of aromatic rings. With said aim in mind, we have synthesized a small compound library of new spiro[cycloalkane-pyridazinones] with 36 members. The compounds with this new scaffold may be useful in various drug discovery projects.

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Analysis of the Physicochemical Properties of Acaricides Based on Lipinski's Rule of Five

Journal of Computational Biology ◽

10.1089/cmb.2019.0323 ◽

2020 ◽

Vol 27 (9) ◽

pp. 1397-1406

Author(s):

Xiaoxia Chen ◽

Hao Li ◽

Lichao Tian ◽

Qinwei Li ◽

Jinxiang Luo ◽

...

Keyword(s):

Physicochemical Properties ◽

Lipinski’S Rule ◽

Lipinski’S Rule Of Five

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Sulfonanilide Derivatives in Identifying Novel Aromatase Inhibitors by Applying Docking, Virtual Screening, and MD Simulations Studies

BioMed Research International ◽

10.1155/2017/2105610 ◽

2017 ◽

Vol 2017 ◽

pp. 1-17 ◽

Cited By ~ 11

Author(s):

Shailima Rampogu ◽

Minky Son ◽

Chanin Park ◽

Hyong-Ha Kim ◽

Jung-Keun Suh ◽

...

Keyword(s):

Aromatase Inhibitors ◽

Causes Of Death ◽

Binding Free Energy ◽

Chemical Compounds ◽

Md Simulations ◽

Free Energy Calculations ◽

Lipinski’S Rule ◽

Discovery Studio ◽

Drug Candidates ◽

Lipinski’S Rule Of Five

Breast cancer is one of the leading causes of death noticed in women across the world. Of late the most successful treatments rendered are the use of aromatase inhibitors (AIs). In the current study, a two-way approach for the identification of novel leads has been adapted. 81 chemical compounds were assessed to understand their potentiality against aromatase along with the four known drugs. Docking was performed employing the CDOCKER protocol available on the Discovery Studio (DS v4.5). Exemestane has displayed a higher dock score among the known drug candidates and is labeled as reference. Out of 81 ligands 14 have exhibited higher dock scores than the reference. In the second approach, these 14 compounds were utilized for the generation of the pharmacophore. The validated four-featured pharmacophore was then allowed to screen Chembridge database and the potential Hits were obtained after subjecting them to Lipinski’s rule of five and the ADMET properties. Subsequently, the acquired 3,050 Hits were escalated to molecular docking utilizing GOLD v5.0. Finally, the obtained Hits were consequently represented to be ideal lead candidates that were escalated to the MD simulations and binding free energy calculations. Additionally, the gene-disease association was performed to delineate the associated disease caused by CYP19A1.

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Design of Chalcones of 7-Azaindole as Raf-B Inhibitors

Journal of Advanced Chemical Sciences ◽

10.30799/jacs.183.18040404 ◽

2019 ◽

Vol 4 (4) ◽

pp. 606-608 ◽

Cited By ~ 1

Author(s):

D. Giles ◽

V.N. Saiprabha ◽

G. Yeshna

Keyword(s):

Binding Affinity ◽

Active Site ◽

In Silico ◽

Significant Interaction ◽

Docking Score ◽

Lipinski’S Rule ◽

Lipinski’S Rule Of Five

The present work deals with the design of 7-azaindole derivatives for its Raf-B inhibition. All the designed compounds follows Lipinski’s rule of five. In silico ADME predictions of all the designed compounds suggests that none of the compounds have problem with bioavailability. The compounds were designed on the binding affinity towards the Raf-B inhibition. It was observed that few of the designed compounds were found to have significant interaction with the active site of the receptor. The compounds possessing 3-hydroxyl-2-methyl as substitution in chalcone was found to possess maximum docking score than other designed compounds.

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Mengidentifikasi Peptida Bioaktif Angiotensin Converting Enzyme-inhibitor (ACEi) dari Kasein β Susu Kambing dengan Polimorfismenya Melalui Teknik In Silico

Jurnal Aplikasi Teknologi Pangan ◽

10.17728/jatp.3008 ◽

2019 ◽

Vol 7 (4) ◽

Author(s):

Hermawan Setyo Widodo ◽

Tridjoko Wisnu Murti ◽

Ali Agus ◽

Widodo Widodo

Keyword(s):

Angiotensin Converting Enzyme ◽

In Silico ◽

Digestive Enzymes ◽

Bioactive Peptides ◽

Enzyme Inhibitor ◽

Goat Milk ◽

Bioactive Peptide ◽

Converting Enzyme ◽

Lipinski’S Rule ◽

Lipinski’S Rule Of Five

Susu kambing memiliki komponen protein salah satunya protein β dan secara umum terjadi polimorfisme pada level protein. Perubahan urutan asam amino akibat polimorfisme memungkinkan adanya potensi dihasilkannya peptida bioaktif penghambat enzim pengubah angiotensin (ACEi). Penelitian ini bertujuan untuk menyaring peptida bioaktif yang berpotensi sebagai ACEi dari kasein β kambing beserta polimorfismenya. Penelitian ini dilakukan dengan teknik in silico terhadap sekuen kasein β kambing serta struktur tiga dimensi human testicular ACE. Langkah yang dilakukan dalam penelitian ini meliputi simulasi pemotongan peptida dengan enzim pencernaan (pepsin, tripsin dan kimotripsin), peninjauan karakteristik peptida lalu simulasi docking ligan-reseptor. Tampilan parameter Lipinski’s Rule of Five (Ro5), bioaktivitas dan energi afinitas dipertimbangkan untuk memilih peptida bioaktif. Hasil yang didapat menunjukkan bahwa ditemukan peptida bioaktif yakni INK (Ile-Asp-Lys) yang memiliki kemampuan hampir setara dengan lisinopril (afinitas energi -8,2kkal/mol vs. -8,3kkal/mol). Peptida INK dapat ditemukan dari hasil hidrolisis dari alel A, C, D dan E, sehingga polimorfisme tidak menyebabkan perbedaan produksi peptida bioaktif. Kesimpulan yang dapat diambil yakni kasein β susu kambing jika dicerna dengan enzim pencernaan dapat menghasilkan peptida bioaktif ACEi yakni INK.Identification of Angiotensin Converting Enzyme-inhibitor (ACEi) Bioactive Peptide from Goat Milk β-Casein with It's Polymorphism by In Silico TechniqueAbstractPolymorphism eventually may be occurred at the protein level. Changes in the amino acid sequence due to polymorphism may exhibit a potential action to generate of the angiotensin-converting enzyme inhibitors (ACEi) bioactive peptide. This study is aimed to assess bioactive peptides that have a great potent value as ACEi from goat β casein along with its polymorphism. The research was done by in silico technique on goat β-casein sequence and three-dimensional structure human testicular ACE. Peptide-cutting simulations with digestive enzymes (pepsin, trypsin and chymotrypsin), peptide properties review, then ligand-receptor docking simulations was applied in this research. Appearance of Lipinski's Rule of Five (Ro5), bioactivity and affinity energy were considered for selecting bioactive peptides. The results show that bioactive peptide found as INK (Ile-Asp-Lys) which had similar ability as lisinopril (energy affinity –8.2kcal/mol vs. –8.3kcal/mol). The INK peptides could be found from the hydrolysis resulted in alleles A, C, D and E, therefore polymorphism did not affect the differences of production of bioactive peptides. A conclusion, processed goat milk β casein with digestive enzymes could produce ACEi of INK as bioactive peptide.

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Studi Penambatan Molekuler dan Prediksi ADMET Senyawa Bioaktif Beberapa Jamu Indonesia terhadap SARS-CoV-2 Main Protease (Mpro)

Berkala Ilmiah Mahasiswa Farmasi Indonesia (BIMFI) ◽

10.48177/bimfi.v7i2.45 ◽

2020 ◽

Vol 7 (2) ◽

pp. 24-41

Author(s):

Sheniez Adhitya Yasin ◽

Alya Azzahra ◽

Norman Emil Ramadhan ◽

Vega Mylanda

Keyword(s):

Autodock Vina ◽

Lipinski’S Rule ◽

Main Protease ◽

Lipinski’S Rule Of Five

Coronavirus jenis baru SARS-CoV-2 terus meyebabkan penyakit pernapasan, yang dikenal dengan Coronavirus Disease-2019 (COVID-19). COVID-19 dianggap sebagai penyakit pademi global terbesar pada tahun 2020 dan terapi antiviral COVID-19 masih kurang di seluruh dunia. Penelitian saat ini masih berusaha untuk menemukan terapi potensial untuk penyakit tersebut, termasuk dari senyawa alami. Oleh karena itu, penting untuk mengetahui senyawa herbal apa yang paling efektif untuk melawan virus tersebut. Jamu merupakan obat tradisional yang berasal dari tumbuhan herbal di Indonesia dan memiliki beberapa khasiat obat. Penelitian ini dilakukan dengan tujuan untuk menemukan potensi jamu Indonesia dalam terapi COVID-19. Sebanyak 283 senyawa bioaktif dari jamu Indonesia disaring melalui penapisan berdasarkan parameter Lipinski’s Rule of Five dan prediksi ADMET (Absorpsi, Distribusi, Metabolisme, Eksreksi, dan Toksisitas) menggunakan ProTox-II dan SwissADME. Sebanyak 12 senyawa hasil penapisan kemudian dilanjutkan untuk diuji melalui penambatan molekuler terhadap SARS-CoV-2 Main Protease (Mpro) menggunakan AutoDock Vina. Hasil penelitian ini menunjukkan bahwa Kurkuminol D memiliki energi bebas ikatan (ΔG); sebesar -6,9 kkal/mol; dan konstanta inhibisi (Ki); sebesar 2,99 µM; terendah dibandingkan senyawa hasil penapisan lainnya. Namun, tidak ada senyawa hasil penapisan yang memiliki ΔG lebih rendah daripada ΔG kedua kontrol positif, yaitu sebesar –8,2 kkal/mol (Lopinavir) dan –7,8 kkal/mol (Ritonavir). Walaupun 271 senyawa lain tidak memenuhi syarat dalam penapisan, senyawa tersebut mungkin saja memiliki potensial yang lebih tinggi daripada obat standar. Oleh karena itu, penelitian ini dapat menjadi titik awal dalam proses pengembangan obat terapi COVID-19 dari senyawa alami.

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Docking against Lung cancer protein and Drug-likeliness of Bioactive Compounds from Phymatosorus scolopendria (Burm.F.) Pic. Serm.

International Journal of Pharmaceutical Sciences and Drug Research ◽

10.25004/ijpsdr.2020.120502 ◽

2020 ◽

pp. 437-441

Author(s):

Sujatha Srinivasan ◽

Catharin S. Sivaraman ◽

Ramya R. Issac ◽

Gayathiri Mahalingam ◽

Gnana D. R. Roke

Keyword(s):

Lung Cancer ◽

Bioactive Compounds ◽

Vinyl Ester ◽

In Vivo Studies ◽

Lipinski’S Rule ◽

Lipinski’S Rule Of Five ◽

Gas Chromatography Mass Spectroscopy ◽

Nitrophenyl Ester

Phymatosorus scolopendria (Burm.F.) Pic. Serm. is a medicinally important fern which is used traditionally by various people all over the World. The aim of this research focuses on the docking against lung cancer protein (2ITO) with bioactive compounds of Phymatosorus scolopendria (Burm.F.) Pic. Serm. which is obtained by using Gas Chromatography Mass Spectroscopy. The same compounds were analysed using Lipinski’s rule of five for its pharmacological prediction. The bioactive compounds were further referred for ADMET property to find its pharmacokinetic potency and prediction towards its potential as drug in future. Among the four compounds docked with the Lung cancer protein (2ITO) 4-Nitrophenyl laurate shows high docking score followed by Hexadecanoic acid, 4 Nitrophenyl ester and Myristic acid Vinyl ester. Out of four compounds studied three compounds satisfied the drug-likeliness based on Lipinski’s rule of five. The present work suggests the bioactive compounds of Phymatosorus scolopendria (Burm.F.) Pic. Serm. for further in vitro and in vivo studies for its anticancer benefits especially related to lung cancer.

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In-silico pharmacophore and Molecular Docking based drug discovery against Marburg Virus Viral Protein VP35; A potent of MAVD.

10.1101/2021.07.01.450693 ◽

2021 ◽

Author(s):

Sameer Quazi ◽

Shreelaxmi Gavas ◽

Javed Ahmad Malik ◽

Komal Singh Suman ◽

Zeshan Haider

Keyword(s):

Molecular Docking ◽

Viral Protein ◽

Virus Disease ◽

Antiviral Drug ◽

Computational Approach ◽

Marburg Virus ◽

Online Tool ◽

Lipinski’S Rule ◽

Zinc Database ◽

Lipinski’S Rule Of Five

Marburg virus is a member of filoviridae and spreads severe Marburg hemorrhagic illness in humans and animals. Nowadays, there is no vaccine available that can completely stop the replication of Marburg replication. Therefore, this study is designed to repurpose the effective therapeutic antiviral drug by using a computational approach against exploring the mechanism of Marburg virus Viral protein 35. We have retrieved about 40570 drug-like small compounds from the ZINC database using the "ZINC Pharmer" online tool. Molecular docking of the ligands from the ready-to-dock database has been carried out using MOE. The five drugs have been identified to bind with VP35 possibly. A study was also performed to evaluate the drug-like characteristics of the substances for absorption, distribution, metabolism, and excretion (ADME). The findings clearly showed that ligands are interacting with the MARV VP35 protein. Interestingly, Lipinski's rule of five was observed by all ligands. These findings provide the foundation for reconstituting and utilizing molecules as a possible therapy for Marburg Virus Disease (MVD).

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