Foreword

In modern computational medicinal chemistry, docking and virtual screening methods in drug design play important roles in aiding the pharmaceutical industries place new drugs on the market. In the first chapter of this book the authors review (homology, fragment, consensus, bioisosteric, scafffold, pharmacophore, induced fit, chemogenomics, knowledge, similarity)-based models. In addition, binding affinities, scoring functions, molecular dynamics, water and solvation, simulation of free energies, quantum mechanics/molecular mechanics, molecular fields, molecular shape and virtual screening are discussed. Some hotspots are also discussed (protein docking, stem cells, workflow pipelines, different types of ligands/targets/ interactions, (cloud/high performance/grid)-computing, post-processing, chemical libraries, confidence and the future. Docking/virtual screening programs, recent evaluations/validations/benchmarking and selected applications of various models to drug design are also reviewed.

Comprehension of binding processes, such as drug-receptor interactions, signal transduction process, and cellular recognition, are important for a better comprehension of biological functions. Medicinal Chemistry, in the path of drug discovery, has focused on studies, of the molecular interactions, which are involved in the development of severe disease states. Consequently, an accurate knowledge of the underlying protein receptor-ligand recognition events at atomic levels is important in the process of comprehension, identification and optimization of more potent drug candidates. In this sense, novel NMR spectroscopic techniques can be used as tools to gain insight into protein-protein and protein-ligand interactions in solution at the molecular level. Resonance signal of the protein or the ligand can be used to identify binding events from these experiments. In Chapter 2 the authors discuss the main NMR experimental approaches applied to identify and characterize protein-ligand binding affinity, providing a broader and better understanding of how NMR spectroscopy techniques can be employed in a drug discovery process.

Most drug candidate failures that occur during clinical trials are due to inappropriate ADMET properties. In this way, there is a major concern to identify possible ADMET failures during the early stages of drug design projects and optimize such properties in order to reduce time and costs effects. In silico ADMET predictions constitute several strategies that play a central role when considering the task of profiling lead compounds concerning potential ADMET failures. In Chapter 3, authors discuss the computational strategies, methods and softwares currently used to profile ADMET, which can be helpful during drug design.

Bioisosterism is a molecular modification medicinal chemistry strategy applied during drug design projects when a lead compound is available. The concept of bioisisterism is centered at the use of chemical diversity in order to optimize pharmaceutical properties of lead compounds and generate active analogs, replacing problematic substructures inside lead compounds by others with similar physicochemical properties. This can surpass the limitations observed for the original lead compound. Bioisosterism can be a useful strategy in order to optimize lead compounds searching analogs with better selectivity and synthetic accessibility, decreased toxicity, improved pharmacokinetics, enhanced solubility and metabolic stability. In Chapter 4, authors highlight the computational approaches used to identify potential bioisosters, discuss how bioisosterism can be helpful during the design of molecules with better synthetic accessibility, and review the scaffold hopping technique, a novel trend of bioisosterism application intending to identify interchangeable scaffolds among pharmaceutical interesting molecules.

This book thus attempts to convey a few selected topics stimulating the fascination of working in all the multidisciplinary areas, which overlaps knowledge of chemistry, physics, biochemistry, biology and pharmacology, describing some of the theoretical and experimental methods in Medicinal Chemistry.