A perspective on multi-target drug discovery and design for complex diseases

Rona R Ramsay,Maria Laura Bolognesi,Elisa Uliassi,Marija R Popovic‐Nikolic,Katarina Nikolic

doi:10.1186/s40169-017-0181-2

Abstract

Diseases of infection, of neurodegeneration (such as Alzheimer’s and Parkinson’s diseases), and of malignancy (cancers) have complex and varied causative factors. Modern drug discovery has the power to identify potential modulators for multiple targets from millions of compounds. Computational approaches allow the determination of the association of each compound with its target before chemical synthesis and biological testing is done. These approaches depend on the prior identification of clinically and biologically validated targets. This Perspective will focus on the molecular and computational approaches that underpin drug design by medicinal chemists to promote understanding and collaboration with clinical scientists.

Highlights

Drug discovery in the 21st century has the disadvantage that it is very difficult to get new compounds into the clinic
Molecular modeling analysis and docking simulations, using the program Autodock Vina and the Protein Data Bank crystal structures of four enzymes (AChE/BuChE/monoamine oxidase (MAO)-A/MAO-B), conducted on a series of experimentally synthesized donepezil-indolyl hybrids [59] and donepezil-pyridyl hybrids [60] revealed that compounds DIH15 [59] and DPH14 [60] expressed the best observed drug-like characteristics and might be considered as a promising compounds for further development for the treatment of Alzheimer’s disease (AD)
There is ongoing need to find more effective drugs to treat infection where adaptation of the invader resulting in resistance is a problem, to combat cancer where advanced understanding of the mechanisms requires selective combinations for specific cancers, and to halt progression in AD where only symptomatic therapies are available

Summary

Introduction

Drug discovery in the 21st century has the disadvantage that it is very difficult to get new compounds into the clinic. Computational approach to ligand discovery and back validation of hits by docking Rational drug design is extensively applied in the search for novel agents as an efficient tool for hit identification, validation, optimization, and evaluation.

Results

Conclusion