Molecular Modeling Approaches for the Prediction of Selected Pharmacokinetic Properties

2019 ◽  
Vol 18 (26) ◽  
pp. 2230-2238 ◽  
Author(s):  
Emilio S. Petito ◽  
David J.R. Foster ◽  
Michael B. Ward ◽  
Matthew J. Sykes
Keyword(s):  
Molecular Modeling ◽  
In Silico ◽  
Volume Of Distribution ◽  
Future Directions ◽  
Unbound Fraction ◽  
Drug Candidates ◽  
New Methods ◽  
Pharmacokinetic Properties

Poor profiles of potential drug candidates, including pharmacokinetic properties, have been acknowledged as a significant hindrance to the development of modern therapeutics. Contemporary drug discovery and development would be incomplete without the aid of molecular modeling (in-silico) techniques, allowing the prediction of pharmacokinetic properties such as clearance, unbound fraction, volume of distribution and bioavailability. As with all models, in-silico approaches are subject to their interpretability, a trait that must be balanced with accuracy when considering the development of new methods. The best models will always require reliable data to inform them, presenting significant challenges, particularly when appropriate in-vitro or in-vivo data may be difficult or time-consuming to obtain. This article seeks to review some of the key in-silico techniques used to predict key pharmacokinetic properties and give commentary on the current and future directions of the field.

scholarly journals Predicting Absorption-Distribution Properties of Neuroprotective Phosphine-Borane Compounds Using In Silico Modeling and Machine Learning

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2505
Author(s):  
Raheem Remtulla ◽  
Sanjoy Kumar Das ◽  
Leonard A. Levin
Keyword(s):  
Machine Learning ◽  
Neural Networks ◽  
In Silico ◽  
Disulfide Bonds ◽  
Oral Absorption ◽  
In Vivo Studies ◽  
Drug Candidates ◽  
In Silico Methods

Phosphine-borane complexes are novel chemical entities with preclinical efficacy in neuronal and ophthalmic disease models. In vitro and in vivo studies showed that the metabolites of these compounds are capable of cleaving disulfide bonds implicated in the downstream effects of axonal injury. A difficulty in using standard in silico methods for studying these drugs is that most computational tools are not designed for borane-containing compounds. Using in silico and machine learning methodologies, the absorption-distribution properties of these unique compounds were assessed. Features examined with in silico methods included cellular permeability, octanol-water partition coefficient, blood-brain barrier permeability, oral absorption and serum protein binding. The resultant neural networks demonstrated an appropriate level of accuracy and were comparable to existing in silico methodologies. Specifically, they were able to reliably predict pharmacokinetic features of known boron-containing compounds. These methods predicted that phosphine-borane compounds and their metabolites meet the necessary pharmacokinetic features for orally active drug candidates. This study showed that the combination of standard in silico predictive and machine learning models with neural networks is effective in predicting pharmacokinetic features of novel boron-containing compounds as neuroprotective drugs.

scholarly journals The Phenoxyalkyltriazine Antagonists for 5-HT6 Receptor with Promising Procognitive and Pharmacokinetic Properties In Vivo in Search for a Novel Therapeutic Approach to Dementia Diseases

2021 ◽  
Vol 22 (19) ◽  
pp. 10773
Author(s):  
Sylwia Sudoł ◽  
Agnieszka Cios ◽  
Magdalena Jastrzębska-Więsek ◽  
Ewelina Honkisz-Orzechowska ◽  
Barbara Mordyl ◽  
...  
Keyword(s):  
Therapeutic Approach ◽  
Cognitive Disorders ◽  
Drug Candidates ◽  
Piperazine Derivatives ◽  
Pharmacokinetic Properties ◽  
Chemical Class ◽  
Novel Therapeutic ◽  
Dementia Diseases

Among the serotonin receptors, one of the most recently discovered 5-HT6 subtype is an important protein target and its ligands may play a key role in the innovative treatment of cognitive disorders. However, none of its selective ligands have reached the pharmaceutical market yet. Recently, a new chemical class of potent 5-HT6 receptor agents, the 1,3,5-triazine-piperazine derivatives, has been synthesized. Three members, the ortho and meta dichloro- (1,2) and the unsubstituted phenyl (3) derivatives, proved to be of special interest due to their high affinities (1,2) and selectivity (3) toward 5-HT6 receptor.. Thus, a broader pharmacological profile for 1–3, including comprehensive screening of the receptor selectivity and drug-like parameters in vitro as well as both, pharmacokinetic and pharmacodynamic properties in vivo, have been investigated within this study. A comprehensive analysis of the obtained results indicated significant procognitive-like activity together with beneficial drug-likeness in vitro and pharmacokinetics in vivo profiles for both, (RS)-4-[1-(2,3-dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (2) and (RS)-4-(4-methylpiperazin-1-yl)-6-(1-phenoxypropyl)-1,3,5-triazin-2-amine (3), but insensibly predominant for compound 2. Nevertheless, both compounds (2 and 3) seem to be good Central Nervous System drug candidates in search for novel therapeutic approach to dementia diseases, based on the 5-HT6 receptor target.

scholarly journals in Silico Docking and Molecular Dynamic Simulation of 3-Dehydroquinate Dehydratase from Mycobacterium Tuberculosis Through Virtual Screening and Pharmacokinetics Studies

2020 ◽  
Author(s):  
Mustafa Alhaji Isa ◽  
Muhammad M Ibrahim
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Virtual Screening ◽  
Molecular Dynamic ◽  
In Silico ◽  
Md Simulation ◽  
Binding Energies ◽  
In Silico Docking ◽  
Pharmacokinetic Properties

The 3-hydroquinate synthase (DHQase) is an enzyme that catalyzes the third step of the shikimate pathway in <i>Mycobacterium tuberculosis</i> (MTB), by converting 3-dehydroquinate into 3-dehydroshikimate. In this study, the novel inhibitors of DHQase from MTB was identified using in silico approach. The crystal structure of DHQase bound to 1,3,4-trihydroxy-5-(3-phenoxypropyl)-cyclohexane-1-carboxylic acid (CA) obtained from the Protein Data Bank (PDB ID: 3N76). The structure prepared through energy minimization and structure optimization. A total of 9699 compounds obtained from Zinc and PubChem databases capable of binding to DHQase and subjected to virtual screening through Lipinski’s rule of five and molecular docking analysis. Eight (8) compounds with good binding energies, ranged between ─8.99 to ─8.39kcal/mol were selected, better than the binding energy of ─4.93kcal/mol for CA and further filtered for pharmacokinetic properties (Absorption, Distribution, Metabolism, Excretion, and Toxicity or ADMET). Five compounds (ZINC14981770, ZINC14741224, ZINC14743698, ZINC13165465, and ZINC8442077) which had desirable pharmacokinetic properties selected for molecular dynamic (MD) simulation and molecular generalized born surface area (MM-GBSA) analyses. The results of the analyses showed that all the compounds formed stable and rigid complexes after the 50ns MD simulation and also had a lower binding as compared to CA. Therefore, these compounds considered as good inhibitors of MTB after in vitro and in vivo validation.”

scholarly journals In Vitro and In Vivo Activities of Synthetic Trioxolanes against Major Human Schistosome Species

2007 ◽  
Vol 51 (4) ◽  
pp. 1440-1445 ◽  
Author(s):  
Shu-Hua Xiao ◽  
Jennifer Keiser ◽  
Jacques Chollet ◽  
Jürg Utzinger ◽  
Yuxiang Dong ◽  
...  
Keyword(s):  
Motor Activity ◽  
Worm Burden ◽  
Female Worm ◽  
Infection Model ◽  
Drug Candidates ◽  
Pharmacokinetic Properties ◽  
Health Significance ◽  
Low Toxicity

ABSTRACT Schistosomiasis is a parasitic disease that remains of considerable public health significance in tropical and subtropical environments. Since the mainstay of schistosomiasis control is chemotherapy with a single drug, praziquantel, drug resistance is a concern. Here, we present new data on the antischistosomal properties of representative synthetic 1,2,4-trioxolanes (OZs). Exposure of adult Schistosoma mansoni for 24 h to a medium containing 20 μg/ml OZ209 reduced worm motor activity, induced tegumental alterations, and killed worms within 72 h. While exposure of S. mansoni to OZ78 had no apparent effect, addition of hemin reduced worm motor activity and caused tegumental damage. Administration of single 200-mg/kg of body weight oral doses of OZ78, OZ209, and OZ288 to mice harboring a juvenile S. mansoni infection resulted in worm burden reductions of 82.0 to 95.4%. In the adult infection model in mice, single 400-mg/kg doses of these compounds resulted in a maximum total worm burden reduction of 52.2%. High worm burden reductions (71.7 to 86.5%) were observed after administration of single 200-mg/kg doses of OZ78 and OZ288 to hamsters infected with either juvenile or adult S. mansoni. A single 200-mg/kg dose of OZ78 to hamsters infected with adult Schistosoma japonicum resulted in total and female worm burden reductions of 94.2 to 100%. Our results, along with the low toxicity, metabolic stability, and good pharmacokinetic properties of the OZs, indicate the potential for the development of novel broad-spectrum antischistosomal OZ drug candidates.

scholarly journals Activities ofN,N′-Diarylurea MMV665852 Analogs against Schistosoma mansoni

2015 ◽  
Vol 59 (4) ◽  
pp. 1935-1941 ◽  
Author(s):  
Noemi Cowan ◽  
Philipp Dätwyler ◽  
Beat Ernst ◽  
Chunkai Wang ◽  
Jonathan L. Vennerstrom ◽  
...  
Keyword(s):  
Physicochemical Properties ◽  
Schistosoma Mansoni ◽  
In Silico ◽  
Worm Burden ◽  
Unmet Need ◽  
Intestinal Wall ◽  
Content Type ◽  
Pharmacokinetic Properties

ABSTRACTThere is an unmet need to discover and develop novel antischistosomal drugs. As exemplified by MMV665852,N,N′-diarylureas have recently emerged as a promising antischistosomal chemotype. In this study, we evaluated the structure-activity relationships of 46 commercially available analogs of MMV665852 on newly transformed schistosomula (NTS) and adultSchistosoma mansoniwormsin vitro. Active compounds were evaluated with a cytotoxicity assay,in silicocalculations, metabolic stability studies, and anin vivoassay with mice harboring adultS. mansoniworms. Of the 46 compounds tested at 33.3 μM, 13 and 14 compounds killed NTS and adult worms, respectively, within 72 h. Nine compounds had 90% inhibitory concentrations (IC90s) of ≤10 μM against adult worms, with selectivity indexes of ≥2.8. Their physicochemical properties and permeation through an artificial membrane indicated good to moderate intestinal absorption. Their metabolic stabilities ranged from low to high. Despite satisfactoryin vitroresults andin silicopredictions, only one compound resulted in a statistically significant worm burden reduction (66%) after administration of a single oral dose of 400 mg/kg of body weight toS. mansoni-infected mice. Worm burden reductions of 0 to 43% were observed for the remaining eight compounds tested. In conclusion, several analogs of theN,N′-diarylurea MMV665852 had high efficacy againstS. mansoniin vitroand favorable physicochemical properties for permeation through the intestinal wall. To counteract the low efficacy observed in the mouse model, further investigations should focus on identifying compounds with improved solubility and pharmacokinetic properties.

scholarly journals In vitro antineurodegenerative activity and in silico predictions of blood-brain barrier penetration of Helichrysum plicatum flower extract

2020 ◽  
pp. 45-51
Author(s):  
Miloš Jovanović ◽  
Zorica Drinić ◽  
Dubravka Bigović ◽  
Ana Alimpić-Aradski ◽  
Sonja Duletić-Laušević ◽  
...  
Keyword(s):  
Antioxidant Activity ◽  
Blood Brain Barrier ◽  
In Silico ◽  
Brain Barrier ◽  
Pharmacokinetic Parameters ◽  
Drug Candidates ◽  
Flower Extract ◽  
Blood Brain ◽  
Pharmacokinetic Properties

This study aimed to assess the antineurodegenerative and antioxidant activity of Helichrysum plicatum flower extract, as well as to identify extract ingredients with acceptable pharmacokinetic parameters such as gastrointestinal absorption, blood-brain barrier permeation, and P-glycoprotein-mediated effusion for optimal therapeutic brain exposure. Antioxidant activity was evaluated by ABTS, FRAP, and b-carotene bleaching assays, while antineurodegenerative activity was tested using acetylcholinesterase (AChE) and tyrosinase (TYR) inhibitory activity assays. In the ABTS test, the dry extract at the highest applied concentration (500 µg/mL) showed better or similar antioxidant activity compared to the standards. In the b-carotene assay, all applied concentrations of the extract showed significantly higher activity than vitamin C. No concentration-dependent activity was observed in the AChE assay, while in the TYR assay the lowest extract concentration (100 µg/mL) showed the highest percentage of inhibition (27.92 %). Pharmacokinetic parameters of compounds were predicted by in silico SwissADME online tool in accordance by the rules of drug-likeness. According to the pharmacokinetic properties, we concluded that pentoxymethoxylated flavones may represent CNS drug candidates for further studies.

scholarly journals In Vitro, In Silico, and In Vivo Assessments of Pharmacokinetic Properties of ZM241385

Molecules ◽  
2020 ◽  
Vol 25 (5) ◽  
pp. 1106 ◽  
Author(s):  
Jin-Ju Byeon ◽  
Min-Ho Park ◽  
Seok-Ho Shin ◽  
Yuri Park ◽  
Byeong ill Lee ◽  
...  
Keyword(s):  
In Silico ◽  
Hepatic Clearance ◽  
Brain Regions ◽  
Rat Plasma ◽  
Pbpk Modeling ◽  
Pharmacokinetic Properties ◽  
Low Exposure

Parkinson’s disease is one of the most common neurodegenerative diseases. Adenosine regulates the response to other neurotransmitters in the brain regions related to motor function. In the several subtypes of adenosine receptors, especially, adenosine 2A receptors (A2ARs) are involved in neurodegenerative conditions. ZM241385 is one of the selective non-xanthine A2AR antagonists with high affinity in the nanomolar range. This study describes the in vitro and in vivo pharmacokinetic properties of ZM241385 in rats. A liquid chromatography-quadrupole time-of-flight mass spectrometric (LC-qToF MS) method was developed for the determination of ZM241385 in rat plasma. In vivo IV administration studies showed that ZM241385 was rapidly eliminated in rats. However, the result of in vitro metabolic stability studies showed that ZM241385 had moderate clearance, suggesting that there is an extra clearance pathway in addition to hepatic clearance. In addition, in vivo PO administration studies demonstrated that ZM241385 had low exposure in rats. The results of semi-mass balance studies and the in silico PBPK modeling studies suggested that the low bioavailability of ZM241385 after oral administration in rats was due to the metabolism and by liver, kidney, and gut.

scholarly journals In silicoidentification of novel peptides with antibacterial activity against multidrug resistantStaphylococcus aureus

2019 ◽  
Author(s):  
Linda B Oyama ◽  
Hamza Olleik ◽  
Ana Carolina Nery Teixeira ◽  
Matheus M Guidini ◽  
James A Pickup ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Peptides ◽  
In Silico ◽  
Multidrug Resistant ◽  
Biofilm Inhibition ◽  
Methicillin Resistant ◽  
Drug Candidates ◽  
Wide Range

AbstractHerein we report the identification and characterisation of two linear antimicrobial peptides (AMPs), HG2 and HG4, with activity against a wide range of multidrug resistant (MDR) bacteria, especially methicillin resistantStaphylococcus aureus(MRSA) strains, a highly problematic group of Gram-positive bacteria in the hospital and community environment. To identify the novel AMPs presented here, we employed the classifier model design, a feature extraction method using molecular descriptors for amino acids for the analysis, visualization, and interpretation of AMP activities from a rumen metagenomic dataset. This allowed for thein silicodiscrimination of active and inactive peptides in order to define a small number of promising novel lead AMP test candidates for chemical synthesis and experimental evaluation.In vitrodata suggest that the chosen AMPs are fast acting, show strong biofilm inhibition and dispersal activity and are efficacious in anin vivomodel of MRSA USA300 infection, whilst showing little toxicity to human erythrocytes and human primary cell linesex vivo. Observations from biophysical AMP-lipid-interactions and electron microscopy suggest that the newly identified peptides interact with the cell membrane and may be involved in the inhibition of other cellular processes. Amphiphilic conformations associated with membrane disruption are also observed in 3D molecular modelling of the peptides. HG2 and HG4 both preferentially bind to MRSA total lipids rather than with human cell lipids indicating that HG4 may form superior templates for safer therapeutic candidates for MDR bacterial infections.Author SummaryWe are losing our ability to treat multidrug resistant (MDR) bacteria, otherwise known as superbugs. This poses a serious global threat to human health as bacteria are increasingly acquiring resistance to antibiotics. There is therefore urgent need to intensify our efforts to develop new safer alternative drug candidates. We emphasise the usefulness of complementing wet-lab andin silicotechniques for the rapid identification of new drug candidates from environmental samples, especially antimicrobial peptides (AMPs). HG2 and HG4, the AMPs identified in our study show promise as effective therapies for the treatment of methicillin resistantStaphylococcus aureusinfections bothin vitroandin vivowhilst having little cytotoxicity against human primary cells, a step forward in the fight against MDR infections.

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