scholarly journals Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

Processes ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 71
Author(s):  
Outi M. H. Salo-Ahen ◽  
Ida Alanko ◽  
Rajendra Bhadane ◽  
Alexandre M. J. J. Bonvin ◽  
Rodrigo Vargas Honorato ◽  
...  

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.

2021 ◽  
Vol 27 ◽  
Author(s):  
Madhu Yadav ◽  
Ritika Srivastava ◽  
Farha Naaz ◽  
Rajesh Verma ◽  
Ramendra K. Singh

Background: Traditionally, various plant extracts having interesting biological properties were the main source of new drugs. In the last 30 years, the role of chemistry in combination with new technologies, like various computational techniques in chemistry, has witnessed a major upsurge in drug discovery and targeted drug delivery. Objective: This article provides a succinct overview of recent techniques of chemistry that have a great impact on the drug development process in general and also against HIV/AIDS. It focuses on new methods employed for drug development with an emphasis on in silico studies, including identifying drug targets, especially the proteins associated with specific diseases. Methods: The rational drug development process starts with the identification of a drug target as the first phase, which helps in the computer-assisted design of new drug molecules. Synthetic chemistry has a major impact on the drug development process because it provides new molecules for future study. Natural products based semisynthesis or microwave assisted synthesis is also involved in developing newly designed drug molecules. Further, the role of analytical chemistry involves extraction, fractionation, isolation and characterization of newly synthesized molecules. Results: Chemistry plays a key role in drug discovery and delivery by natural process or with the help of synthetic nanoparticles or nanomedicines. So, nanochemistry is also deeply involved in the development of new drugs and their applications. Conclusion: The previous era of drug discovery was dominated only by chemistry, but the modern approaches involve a comprehensive knowledge of synthetic chemistry, medicinal chemistry, computational chemistry and the concerned biological phenomenon.


2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Anna Lucia Fallacara ◽  
Iuni Margaret Laura Tris ◽  
Amalia Belfiore ◽  
Maurizio Botta

The Drug development process has undergone a great change over the years. The way, from haphazard discovery of new natural products with a potent biological activity to a rational design of small molecule effective against a selected target, has been long and sprinkled with difficulties. The oldest drug development models are widely perceived as opaque and inefficient, with the cost of research and development continuing to rise even if the production of new drugs remains constant. The present paper, will give an overview of the principles, approaches, processes, and status of drug discovery today with an eye towards the past and the future.


2003 ◽  
Vol 28 (1) ◽  
pp. 87-106 ◽  
Author(s):  
Anne G. Evans ◽  
Nikhil P. Varaiya

This case describes Anne Evans’ search for a market opportunity in the biotechnology industry, and examines the feasibility of establishing a new venture to exploit this opportunity. The drug development process in the biopharmaceutical industry spans three critical phases: pharmaceutical discovery, pharmaceutical development, and product marketing. The drug development process is a very capital–intensive process with expenditures averaging $800 million per drug and with very high failure rates—only one out of 5,000 compounds that emerge from discovery and preclinical testing will make it into the market. The drug development process therefore contributes to very high cash burn rates and corporate failures in the biotechnology industry.


Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 812 ◽  
Author(s):  
Veronica Salmaso ◽  
Kenneth A. Jacobson

Molecular modeling has contributed to drug discovery for purinergic GPCRs, including adenosine receptors (ARs) and P2Y receptors (P2YRs). Experimental structures and homology modeling have proven to be useful in understanding and predicting structure activity relationships (SAR) of agonists and antagonists. This review provides an excursus on molecular dynamics (MD) simulations applied to ARs and P2YRs. The binding modes of newly synthesized A1AR- and A3AR-selective nucleoside derivatives, potentially of use against depression and inflammation, respectively, have been predicted to recapitulate their SAR and the species dependence of A3AR affinity. P2Y12R and P2Y1R crystallographic structures, respectively, have provided a detailed understanding of the recognition of anti-inflammatory P2Y14R antagonists and a large group of allosteric and orthosteric antagonists of P2Y1R, an antithrombotic and neuroprotective target. MD of A2AAR (an anticancer and neuroprotective target), A3AR, and P2Y1R has identified microswitches that are putatively involved in receptor activation. The approach pathways of different ligands toward A2AAR and P2Y1R binding sites have also been explored. A1AR, A2AAR, and A3AR were utilizes to study allosteric phenomena, but locating the binding site of structurally diverse allosteric modulators, such as an A3AR enhancer LUF6000, is challenging. Ligand residence time, a predictor of in vivo efficacy, and the structural role of water were investigated through A2AAR MD simulations. Thus, new MD and other modeling algorithms have contributed to purinergic GPCR drug discovery.


2019 ◽  
Vol 1 (6) ◽  
pp. 253-257
Author(s):  
Thenmozhi M ◽  
Murugesan A ◽  
Kumaravel S.T

Vitiligo is an epidermal disorder causes depigmented patches resulted from the loss of melanocytes, Autoimmunity hypotheses strongly supports that the immune system compartments responsible in the development of vitiligo. Adenosine MonoPhosphate kinase (AMPK) signaling plays a role in regimentation in vitiligo. In this present study, set of ligands selected to dock against AMPK protein in the AMP binding site using FlexX software. Based on the scores and protein-ligand interactions selected ligands were analyzed for its binding affinity and protein ligand stability for its further drug development process.


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