Molecular dynamics (MD) simulations have become increasingly useful in the modern drug development process. In this review, we give a broad overview of the current application possibilities of MD in drug discovery and pharmaceutical development. Starting from the target validation step of the drug development process, we give several examples of how MD studies can give important insights into the dynamics and function of identified drug targets such as sirtuins, RAS proteins, or intrinsically disordered proteins. The role of MD in antibody design is also reviewed. In the lead discovery and lead optimization phases, MD facilitates the evaluation of the binding energetics and kinetics of the ligand-receptor interactions, therefore guiding the choice of the best candidate molecules for further development. The importance of considering the biological lipid bilayer environment in the MD simulations of membrane proteins is also discussed, using G-protein coupled receptors and ion channels as well as the drug-metabolizing cytochrome P450 enzymes as relevant examples. Lastly, we discuss the emerging role of MD simulations in facilitating the pharmaceutical formulation development of drugs and candidate drugs. Specifically, we look at how MD can be used in studying the crystalline and amorphous solids, the stability of amorphous drug or drug-polymer formulations, and drug solubility. Moreover, since nanoparticle drug formulations are of great interest in the field of drug delivery research, different applications of nano-particle simulations are also briefly summarized using multiple recent studies as examples. In the future, the role of MD simulations in facilitating the drug development process is likely to grow substantially with the increasing computer power and advancements in the development of force fields and enhanced MD methodologies.

Chemokine receptors are key regulators of cell migration in terms of immunity and inflammation. Among these, CCR5 and CXCR4 play pivotal roles in cancer metastasis and HIV-1 transmission and infection. They act as essential co-receptors for HIV and furnish a route to the cell entry. In particular, inhibition of either CCR5 or CXCR4 leads very often the virus to shift to a more virulent dual-tropic strain. Therefore, dual receptor inhibition might improve the therapeutic strategies against HIV. In this study, we aimed to discover selective CCR5, CXCR4, and dual CCR5/CXCR4 antagonists using both receptor- and ligand-based computational methods. We employed this approach to fully incorporate the interaction attributes of the binding pocket together with molecular dynamics (MD) simulations and binding free energy calculations. The best hits were evaluated for their anti-HIV-1 activity against CXCR4- and CCR5-specific NL4.3 and BaL strains. Moreover, the Ca 2+ mobilization assay was used to evaluate their antagonistic activity. From the 27 tested compounds, three were identified as inhibitors: compounds 27 (CCR5), 6 (CXCR4) and 3 (dual) with IC 50 values ranging from 10.64 to 64.56 μM. The binding mode analysis suggests that the active compounds form a salt bridge with the glutamates and π-stacking interactions with the aromatic side chains binding site residues of the respective co-receptor. The presented hierarchical virtual screening approach provides essential aspects in identifying potential antagonists in terms of selectivity against a specific co-receptor. The compounds having multiple heterocyclic nitrogen atoms proved to be relatively more specific towards CXCR4 inhibition as compared to CCR5. The identified compounds serve as a starting point for further development of HIV entry inhibitors through synthesis and quantitative structure-activity relationship studies.

Abstract:Fifteen compounds related to ameltolide with sodium channel inhibitory activity were subjected to a molecular docking study. The chemical structures of all compounds were built using the program HyperChem and conformational studies were performed with a semiempirical method followed by the PM3 method. A docking study was performed using the program AutoDock on all the compounds. To confirm the binding mode of inhibitors, molecular dynamics simulations were performed using GROMACS 4.5.5, based upon the docked conformation of ameltolide. The docking analyses indicated that these compounds interacted mainly with residues II-S6 and III-S6 of NaV1.2 by making hydrogen bonds and ( π − π) interactions with domains I, III, and IV in the channel's inner pore. Our docking study reveals that amide linker plays a major role in the drug-receptor interaction. The results of molecular dynamic simulations confirmed the binding mode of ligands, the accuracy of docking, and the reliability of active conformations obtained by AutoDock.

Stilbenes are plant polyphenols that have shown beneficial pharmacological activities in a variety of diseases. The considerable amount of stilbene glucosides in spruce inner bark encouraged us to develop a straightforward and simple method of extraction with high recovery and yield. Stilbene glucosides from fresh inner bark of Norway spruce were extracted in one simple step with acetone at 20 °C. After three weeks of soaking in acetone, the extracts were dried and the composition was determined by GC-FID using a short and a long column (HP-5) and GC-MS (HP-1). The amount of the extracted compounds was also compared with a similar extract from air dried inner bark samples. The extracts from the fresh sample contained 30–50% of stilbene glucosides and the average yield [0.185 g extract/g bark] was as good as or slightly better than in previously reported works. However, no drying, milling, or sequential extractions with different solvents in elevated temperatures were needed. Moreover, this study revealed that the drying process can decrease the amount of extractable stilbenes significantly. Therefore, this method can be considered as an alternative for preparative isolation of stilbene glucosides, especially isorhapontin and astringin from inner bark of Norway spruce.

Background: A series of phthalimides related to thalidomide have been studied for analgesic activity in the formalin test. The formalin test was performed in mice in a nociceptive pattern to evaluate analgesic activity. background: The formalin test which is done in mouse is an authoritative pattern of nociception to evaluate analgesic activity. In this study nine derivatives of phthalimides were evaluated as analgesic effect in mice.They have significant analgesic effect compared with indomethacin and negative control. Methods: In this study, nine derivatives of phthalimides were evaluated in terms of exerting analgesic effects in mice. They exerted significant analgesic effects compared to indomethacin and negative control. These compounds were synthesized and characterized by TLC, followed by IR and H1NMR in the previous studies. Two distinct periods of high licking activity were used to analyze both acute and chronic pain. All compounds were compared with indomethacin and carbamazepine as positive control and vehicle as a negative control. objective: Since thalidomide is a multi-drug target, research is continuous. Previous studies have shown that thalidomide directly inhibits COX-1/2 , tumor necrosis factor (TNF-α) and Na channels . Results: All of the tested compounds exhibited significant analgesic activity in both the first and second phases of the test compared to the control group (DMSO), although they did not show more activity than the reference drug (indomethacin) but were comparable to indomethacin. method: These compounds were synthesized and characterized by TLC followed by IR and H1NMR in the previous studies. Two distinct periods of high licking activity were used to analyze both acute and chronic pain. Conclusion: This information may be useful in the development of a more potent phthalimide as an analgesic agent that acts as a sodium channel blocker and COX inhibitor. other: This information may be useful in the development of more potent phthalimide as an analgesic agent that act as sodium channel blockers and COX-inhibitor.

Using a model of the Na channel, these derivatives were docked in the active site. Docking studies displayed that all synthesized compounds have more negative binding energy compare to reference drug and inhibition-constant less than phenytoin that means they can block the receptor more efficiently and usually form hydrophobic interactions or hydrogen bond interaction frequently with the domains I, II, III and rarely with domain IV.

The authors regret that the Acknowledgements section was missing from the original published version of the article. Acknowledgement should have been published as below.