Anticancer Potency of Dimethyl 2-(2-Hydroxy-2-Methoxypropilidine) Malonate in Kombucha

Kombucha has an anticancer potency because it has dimethyl 2-(2-hydroxy-2-methoxypropilidine) malonate compound. The research aimed to verify the compound dimethyl 2-(2-hydroxy-2-methoxypropilidine) malonate as an anticancer with the in-silico method, namely the molecular docking approach, drug likeness profile, and ADMET test. The tools used were the PyRx, Discovery Studio Visualizer, Sanjeevini, and pkCSM. The research material consisted of 3D Dimethyl 2-(2-Hydroxy-2-Methoxypropilidine) Malonate and Epidermal Growth Factor Receptor (EGFR). The analysis showed Dimethyl 2-(2-Hydroxy-2-Methoxypropilidine) Malonate is safe for consumption and can suppress cancer cells.

DOGS: Reaction-Driven de novo Design of Bioactive Compounds

We present a computational method for the reaction-based de novo design of drug-like molecules. The software DOGS (Design of Genuine Structures) features a ligand-based strategy for automated ‘in silico’ assembly of potentially novel bioactive compounds. The quality of the designed compounds is assessed by a graph kernel method measuring their similarity to known bioactive reference ligands in terms of structural and pharmacophoric features. We implemented a deterministic compound construction procedure that explicitly considers compound synthesizability, based on a compilation of 25'144 readily available synthetic building blocks and 58 established reaction principles. This enables the software to suggest a synthesis route for each designed compound. Two prospective case studies are presented together with details on the algorithm and its implementation. De novo designed ligand candidates for the human histamine H4 receptor and γ-secretase were synthesized as suggested by the software. The computational approach proved to be suitable for scaffold-hopping from known ligands to novel chemotypes, and for generating bioactive molecules with drug-like properties

Molecular topology, a novel descriptor for compound quality assessment

Abstract The pharmaceutical industry is currently facing a high clinical attrition rate. In order to prevent the late-stage clinical failure, many investigations on compound quality and drug-likeness of compounds have been carried out. It has been widely accepted that molecular size and lipophilicity plays an important role in compound quality. Many attempts have been done to find out other factors which can influence compound quality beyond size and lipophilicity. Recently, a molecular topology concept has been put forward and its influence on compound quality has been investigated. It has been shown that drugs have higher fraction of compounds with only one ring system compared to clinical candidate and bioactive compounds. As an extension to the previous studies, the aim of this project is to further investigate how the molecular topology influences some of the most important physicochemical properties of molecules as well as the compound potency efficiency indices in general. Our results show that among reported molecules in the literature, compounds with only one ring system are smaller in size, less lipophilic and therefore has a higher probability to be less toxic. Interestingly compounds which have a simple topology also show advantage in terms of potency efficiency such as ligand efficiency (LE), ligand lipophilic efficiency (LLE) and ligand-efficiency-dependent lipophilicity index (LELP) compared with compounds which have a more complex topology. Thus a novel hypothesis why compounds with only one ring system are abundant among drugs has been proposed. On average molecules with only one ring system seems to bind more strongly to its protein target; this might reduce the necessary size of the molecule to reach a certain potency level. The reduction in size and lipophilicity reduces the risk of failure in clinical trials. Popular science summary: Molecular topology, A novel descriptor for compound quality assessment Drug discovery and development is a time consuming process which typically takes 15 to 20 years from the target identification until a drug makes it to the market. During this lengthy process, numerous compounds are tested, synthesized and validated in order to achieve the optimal efficacy and safety profile. Historically drug discovery was an iterative process of compound synthesis and in vivo screening. This paradigm has changed by the advancement of in vitro high-throughput screening technology and in silico techniques. The paradigm shift has largely improved hit identification efficiency; however the pharmaceutical industry still faces a high attrition rate. It is critical to identify compounds which are unlikely to succeed (low quality compounds) and to terminate the development of these compounds as early as possible. Recently molecular topology class was proposed; basically, it classifies compounds according to the number of ring systems. It has been reported that the fraction of compounds with only one ring system (1TR) is higher in drugs compared to clinical candidates and general bioactive compounds. This thesis aims to better understand the earlier observation of 1TR compounds’ enrichment in drugs. In this project, how the molecular topology influences some of the most important physicochemical properties of molecules as well as the compound potency efficiency indices was investigated. It showed that among reported molecules in the literature, compounds with only one ring system are smaller in size, less lipophilic and therefore has a higher probability to be less toxic. On average, molecules with only one ring system bind more strongly to its protein target; this reduces the necessary size of the molecule to reach a certain potency level. The reduction in size and lipophilicity reduces the risk of failure in clinical trials. By understanding what properties determine the quality of a compound, it will be possible to deliver drugs to the market more efficiently. Advisor: Ola Engkvist, Hongming Chen (Computational Chemistry, AstraZeneca R&D Mölndal) Master´s Degree Project 60 credits in Bioinformatics, 2011-2012 Department of Biology., Lund Universit

Molecular docking studies of Chenopodium album Linn with Lanosterol synthase enzyme

Cardiovascular diseases (CVD) are the major cause of death among people across the globe.  Hypercholesterolemia is one of the major contributing factors for CVD. Molecules that bind with Lanosterol synthase enzyme, can be potential drug targets.  Statin group of compounds like Simvastatin, cerivastatin, Atorvastatin etc., used for treating hypercholesterolemia have side effects and hence there is a growing demand for plant derived flavonoids.  This work focusses on studying the compounds quercetin-3-O-(2??,6??-di-O-?-l-rhamnopyranosyl)-?-d-glucopyranoside, kaempferol-3-O-(2??,6??-di-O-?-l-rhamnopyranosyl)-?-d-glucopyranoside, rutin; quercetin-3-O-?-d-glucopyranoside (Iso quercetin); and kaempferol-3-O-?-d-glucopyranoside (Astragalin) present in Chenopodium album Linn to inhibit Lanosterol synthase.   Bioactivity score, drug likeness character was assessed in silico.  Based on bioactivity spectrum, it is observed that the molecules are biologically active and the probability of these compounds to be biologically active is ranging from 0.784 to 0.992, suggesting that these compounds are effective for treating hypercholesterolemia.   In the molecular docking studies, the compounds binding affinity score was in agreement that the molecules have the potential to be used as an alternative to the statin group of compounds in treating cholesterol

MOLECULAR DOCKING STUDIES ON THE THERAPEUTIC TARGETS OF ALZHEIMER'S DISEASE (AChE AND BChE) USING NATURAL BIOACTIVE ALKALOIDS

Objective: Alzheimer's disease (AD), a progressive neurodegenerative disorder with many cognitive and neuropsychiatric symptoms, is biochemically characterized by a significant decrease in the brain neurotransmitter Acetylcholine (ACh).Methods: In the present insilico study, six plant bioactive compounds namely Harmol, Vasicine, Harmaline, Harmine, Harmane and Harmalol (from P. Nigellastrum Bunge) were analyzed for their inhibitory role on AChE (Acetylcholinesterase) and BChE (Butyrylcholinesterase) activity by applying the molecular docking studies. Other parameters viz. determination of molecular interaction-based binding affinity values, protein-ligand interactions, Lipinski rule of five, functional properties and biological activities for the above compounds were also calculated by employing the appropriate bioinformatics tools.Results: The results of docking analysis clearly showed that Harmalol has highest binding affinity with AChE (-8.6 kcal/mole) and BChE (-8.0 kcal/mole) but it does not qualified the enzyme inhibitory activity, since it was exerted, and also has least percentage activity on AD and neurodegenerative disease. Whereas, the Harmine has been second qualified binding affinity (-8.4 kcal/mol) and first in other parameters when compared with Harmalol.Conclusion: Based on docking results and other parameters conducted, we are concluding that Harmine is the best compound for further studies to treat AD.Keywords: Alzheimer's disease (AD), Acetylcholinesterase, Butyrylcholinesterase, Lead Molecule