scholarly journals Mechanistic Insights into Passive Membrane Permeability of Drug-Like Molecules from a Weighted Ensemble of Trajectories

2021 ◽  
Author(s):  
She Zhang ◽  
Jeff Thompson ◽  
Junchao Xia ◽  
Anthony Bogetti ◽  
Forrest York ◽  
...  
Keyword(s):  
Membrane Permeability ◽  
Rational Design ◽  
Large Scale ◽  
Sampling Strategy ◽  
Rational Drug Design ◽  
Permeability Coefficients ◽  
Rational Drug ◽  
Pharmacokinetic Properties ◽  
Experimental Values ◽  
Dynamics Simulations

Passive permeability of a drug-like molecule is a critical assay early in a drug discovery campaign that informs a medicinal chemist how well a compound can traverse biological membranes, such as gastrointestinal epithelial or restrictive organ barriers, so it can perform a specific therapeutic function. However, the challenge that remains is the development of a method, experimental or computational, which can both determine the permeation rate and provide mechanistic insights into the transport process to help with the rational design for any given molecule. Typically, one of three methods are used to measure membrane permeability: (1) experimental permeation assays acting on either artificial or natural membranes; (2) quantitative structure-permeability relationship (QSPR) models that rely on experimental values of permeability or related pharmacokinetic properties of a range of molecules to infer those for new molecules; (3) estimates of permeability from the Smoluchowski equation, where free energy and diffusion profiles along the membrane normal are taken as input from large-scale molecular dynamics simulations. While all these methods provide estimates of permeation coefficients, they provide very little information for guiding rational drug design. In this study, we employ a highly parallelizable weighted ensemble (WE) path sampling strategy, empowered by cloud computing techniques, to generate unbiased permeation pathways and permeability coefficients for a set of drug-like molecules across a neat 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC) membrane bilayer. Our WE method predicts permeability coefficients that compare well to experimental values from an MDCK-LE cell line and PAMPA assays for a set of drug-like amines of varying size, shape, and flexibility. Our method also yields a series of continuous permeation pathways weighted and ranked by their associated probabilities. Taken together, the ensemble of reactive permeation pathways, along with the estimate of the permeability coefficient, provides a clearer picture of the microscopic underpinnings of small molecule membrane permeation.

scholarly journals A pharmacological master key mechanism that unlocks the selectivity filter gate in K+channels

Science ◽  
2019 ◽  
Vol 363 (6429) ◽  
pp. 875-880 ◽  
Author(s):  
Marcus Schewe ◽  
Han Sun ◽  
Ümit Mert ◽  
Alexandra Mackenzie ◽  
Ashley C. W. Pike ◽  
...  
Keyword(s):  
Selectivity Filter ◽  
Rational Drug Design ◽  
Related Gene ◽  
K Channels ◽  
X Ray ◽  
Voltage Gated ◽  
X Ray Crystallography ◽  
Rational Drug ◽  
Dynamics Simulations ◽  
Pore Domain

Potassium (K+) channels have been evolutionarily tuned for activation by diverse biological stimuli, and pharmacological activation is thought to target these specific gating mechanisms. Here we report a class of negatively charged activators (NCAs) that bypass the specific mechanisms but act as master keys to open K+channels gated at their selectivity filter (SF), including many two-pore domain K+(K2P) channels, voltage-gated hERG (human ether-à-go-go–related gene) channels and calcium (Ca2+)–activated big-conductance potassium (BK)–type channels. Functional analysis, x-ray crystallography, and molecular dynamics simulations revealed that the NCAs bind to similar sites below the SF, increase pore and SF K+occupancy, and open the filter gate. These results uncover an unrecognized polypharmacology among K+channel activators and highlight a filter gating machinery that is conserved across different families of K+channels with implications for rational drug design.

scholarly journals EXPLORATION OF MICROORGANISMS AS A POTENTIAL SOURCE OF XANTHINE OXIDASE INHIBITORS: AN UPDATED REVIEW

2018 ◽  
Vol 10 (12) ◽  
pp. 1 ◽  
Author(s):  
Uma Rajeswari Batchu ◽  
Joshna Rani Surapaneni
Keyword(s):  
Uric Acid ◽  
Xanthine Oxidase ◽  
Large Scale ◽  
Enzyme Inhibitors ◽  
Rational Drug Design ◽  
Scale Production ◽  
Clinical Investigations ◽  
Large Scale Production ◽  
Xanthine Oxidase Inhibitors ◽  
Rational Drug

Nowadays the prevalence of hyperuricemia has significantly increased in which serum uric acid levels are exceeding the normal range. Gout is the predominant clinical implication of the hyperuricemia, but many clinical investigations have confirmed that hyperuricemia is an independent risk factor for cardiovascular disease (CVD), hypertension, diabetes, and many other diseases. The xanthine oxidase (XO) converts hypoxanthine to xanthine and ultimately to uric acid, and the irreversibly accumulated uric acid causes hyperuricemia associated with gout. Hence specific and selective xanthine oxidase inhibitors (XOI) are potentially powerful tools for inactivating target XO in the pathogenic process of hyperuricemia (Gout). The objective of the current study was to overview the various XOI isolated from the microorganisms. Microorganisms have been employed for several decades for the large-scale production of a variety of bio-chemicals ranging from alcohol to antibiotics and as well as enzyme inhibitors. Currently available XOI (allopurinol and febuxostat) for the treatment of gout have been exhibiting serious side effects. Thus, there is a need to search for new molecules to treat hyperuricemia and its associated disorders. At present, microbes have been unexplored in the development of successful products for the management of XO-related diseases. Hence, the present review focused on novel XOI produced from various microbial species such as Actinobacteria, lichens, bacteria, endophytic fungi and mushrooms, which can be expected to play an important role in the ongoing transition from the empirical screening to the real rational drug design. 

scholarly journals PDB_REDO: automated re-refinement of X-ray structure models in the PDB

2009 ◽  
Vol 42 (3) ◽  
pp. 376-384 ◽  
Author(s):  
Robbie P. Joosten ◽  
Jean Salzemann ◽  
Vincent Bloch ◽  
Heinz Stockinger ◽  
Ann-Charlott Berglund ◽  
...  
Keyword(s):  
Structural Biology ◽  
Large Scale ◽  
Homology Modelling ◽  
Three Dimensional ◽  
Data Bank ◽  
Rational Drug Design ◽  
X Ray ◽  
Rational Drug ◽  
Geometric Quality ◽  
Existing Structure

Structural biology, homology modelling and rational drug design require accurate three-dimensional macromolecular coordinates. However, the coordinates in the Protein Data Bank (PDB) have not all been obtained using the latest experimental and computational methods. In this study a method is presented for automated re-refinement of existing structure models in the PDB. A large-scale benchmark with 16 807 PDB entries showed that they can be improved in terms of fit to the deposited experimental X-ray data as well as in terms of geometric quality. The re-refinement protocol uses TLS models to describe concerted atom movement. The resulting structure models are made available through the PDB_REDO databank (http://www.cmbi.ru.nl/pdb_redo/). Grid computing techniques were used to overcome the computational requirements of this endeavour.

scholarly journals Overcoming mutation-based resistance to antiandrogens with rational drug design

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Minna D Balbas ◽  
Michael J Evans ◽  
David J Hosfield ◽  
John Wongvipat ◽  
Vivek K Arora ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Novel Mutation ◽  
Ectopic Expression ◽  
Rational Drug Design ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Rational Drug ◽  
Duration Of Response ◽  
Helix 12 ◽  
Dynamics Simulations

The second-generation antiandrogen enzalutamide was recently approved for patients with castration-resistant prostate cancer. Despite its success, the duration of response is often limited. For previous antiandrogens, one mechanism of resistance is mutation of the androgen receptor (AR). To prospectively identify AR mutations that might confer resistance to enzalutamide, we performed a reporter-based mutagenesis screen and identified a novel mutation, F876L, which converted enzalutamide into an AR agonist. Ectopic expression of AR F876L rescued the growth inhibition of enzalutamide treatment. Molecular dynamics simulations performed on antiandrogen–AR complexes suggested a mechanism by which the F876L substitution alleviates antagonism through repositioning of the coactivator recruiting helix 12. This model then provided the rationale for a focused chemical screen which, based on existing antiandrogen scaffolds, identified three novel compounds that effectively antagonized AR F876L (and AR WT) to suppress the growth of prostate cancer cells resistant to enzalutamide.

scholarly journals Drug design, discovery and development and their safety or efficacy on human body

2021 ◽  
Vol 17 (2) ◽  
pp. 113-122
Author(s):  
Shamima Shultana ◽  
Kazi M Maraz ◽  
Arwah Ahmed ◽  
Tanzila Sultana ◽  
Ruhul A Khan
Keyword(s):  
Drug Design ◽  
Human Body ◽  
Rational Design ◽  
Organic Molecule ◽  
Molecular Targets ◽  
Molecular Shape ◽  
Therapeutic Benefit ◽  
Target Site ◽  
Rational Drug Design ◽  
Rational Drug

Drug Design, often mentioned as rational drug design or just rational design. It is defined as the study of the shape of molecules in order to determine how they will bind receptors on cells or combine with other molecules. It is based on molecular shape or architecture is an alternative to blindly testing hundreds of molecules to see if one or more of them will bind cellular or molecular targets. The drug is an organic molecule, when it is bind to target site it can either inhibit or activate the function of a bio-molecule which results in therapeutic benefit.

In Silico ADMET Evaluation of Natural DPP-IV Inhibitors for Rational Drug Design against Diabetes

2020 ◽  
Vol 21 (10) ◽  
pp. 768-777
Author(s):  
Rajeev K. Singla ◽  
Bairong Shen
Keyword(s):  
Diabetes Mellitus ◽  
In Silico ◽  
Rational Drug Design ◽  
Diabetic Patients ◽  
Dpp Iv ◽  
Rational Drug ◽  
In Silico Admet ◽  
Pharmacokinetic Properties ◽  
Treatment Of Diabetes ◽  
The Many

Background: As a metabolic and lifestyle disorder, diabetes mellitus poses a prodigious health risk. Out of the many key targets, DPP-IV is one of the very imperative therapeutic targets for the treatment of diabetic patients. Methods: In our current study, we have done the in silico simulations of ADME-T properties for naturally originated potent DPP-IV inhibitors like quinovic acid, stigmasterol, quinovic acid-3-beta-D-glycopyranoside, zygophyloside E, and lupeol. Structural topographies associated with different pharmacokinetic properties have been systematically assessed. Results: Glycosylation on quinovic acid is found to be noteworthy for the improvement of pharmacokinetic and toxicological properties, which leads to the prediction that zygophyloside E can be further tailored down to get the lead DPP-IV inhibitor. Conclusion: This assessment provides useful insight into the future development of novel drugs for the treatment of diabetes mellitus.

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