Author : Wanlei Wei
Publisher :
ISBN 13 :
Total Pages : pages
Book Rating : 4.:/5 (125 download)
Book Synopsis Accelerating Drug Discovery Through Method Developments in Nucleic Acid Docking and Force Fields for Small Molecules by : Wanlei Wei
Download or read book Accelerating Drug Discovery Through Method Developments in Nucleic Acid Docking and Force Fields for Small Molecules written by Wanlei Wei and published by . This book was released on 2021 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "The field of computational chemistry has grown rapidly and is becoming increasingly more sophisticated and accurate over the past few years and decades. Owing to its multidisciplinary nature, it has been applied to a variety of different fields, including drug discovery and medicinal chemistry. Traditionally, drug discovery has been a costly and laborious task, requiring upwards of billions of dollars and decades for each approved pharmaceutical. As a result, increases in efficiency would greatly benefit humanity and the pharmaceutical industry for treating various diseases. To this end, molecular docking methods attempt to reduce the time and labour costs by evaluating the binding of small molecules to proteins or nucleic acid receptors in silico. This is done during the initial drug discovery stages, where billions of pharmaceuticals in a ligand library could be screened virtually, quickly, and inexpensively. Despite the imperfect accuracy of in silico docking, its usefulness arises from its ability to enrich compound libraries, allowing medicinal chemists to select drug candidates, which are most promising for synthesis and testing. This has been applied to a variety of medicinal chemistry projects involving protein targets.Recently, it has been realized that DNAs and RNAs are excellent targets of pharmaceuticals, as evidenced by the discovery of two molecules, branaplam and ribocil. This has ushered in a new era for pharmaceutical companies, known as the “RNA gold rush”. Unfortunately, biochemical differences between nucleic acids and proteins have made it challenging to accurately dock molecules to the former. One of these biochemical differences is attributed to the role of water molecules found and involved in the binding of ligand molecules to nucleic acids, which are rarely found in protein binding sites. Consequently, to improve the accuracy of nucleic acid docking, a method to predict the positions of these water molecules was developed. This method, SPLASH’EM, places water molecules based on a previous statistical survey of water hotspots in existing nucleic acid structures from the Protein Data Bank and also uses a specialized force field. To our knowledge, this method is the first fully automated procedure for water placement and is the only well-validated method to-date, for water placement for nucleic acids. SPLASH’EM was found to have achieved the highest accuracy to-date for predicting tightly-bound water molecules in nucleic acid-ligand complexes.In a parallel effort, further efforts to improve the enrichment capabilities of docking programs was undertaken. This was done by improving the description of the conformational energy landscapes of ligands binding to proteins and nucleic acids. Traditionally, molecular mechanics force fields have been used in place of quantum mechanics during docking, due to their low computational costs, despite losses in accuracy. In particular, the torsional parameters in these molecular mechanics force fields were identified as being poor, as they relied upon a limited number of parameters, called atom-types, which were found to poorly transfer between different molecules. Consequently, a conceptually novel approach was taken to predict torsional parameters, based on chemical principles, without reliance on atom-types. This method, called H-TEQ, was found to significantly outperform the accuracy of existing methods, including GAFF2, MMFF94, and MAB on small druglike molecules. The adoption of H-TEQ to enhance the description of torsional parameters, along with better descriptions of van der Waals and electrostatic interactions, would allow enhancements to the ability of docking programs to correctly identify active compounds, during drug discovery projects"--
