Systems Pharmacology in Small Molecular Drug Discovery.

Wei Zhou,Yonghua Wang,Ge Zhang,Aiping Lu

doi:10.3390/ijms17020246

Abstract

Drug discovery is a risky, costly and time-consuming process depending on multidisciplinary methods to create safe and effective medicines. Although considerable progress has been made by high-throughput screening methods in drug design, the cost of developing contemporary approved drugs did not match that in the past decade. The major reason is the late-stage clinical failures in Phases II and III because of the complicated interactions between drug-specific, human body and environmental aspects affecting the safety and efficacy of a drug. There is a growing hope that systems-level consideration may provide a new perspective to overcome such current difficulties of drug discovery and development. The systems pharmacology method emerged as a holistic approach and has attracted more and more attention recently. The applications of systems pharmacology not only provide the pharmacodynamic evaluation and target identification of drug molecules, but also give a systems-level of understanding the interaction mechanism between drugs and complex disease. Therefore, the present review is an attempt to introduce how holistic systems pharmacology that integrated in silico ADME/T (i.e., absorption, distribution, metabolism, excretion and toxicity), target fishing and network pharmacology facilitates the discovery of small molecular drugs at the system level.

Highlights

Drug discovery is a long and extremely complicated process with a low success rate and vast capital investment
The evidence shows that the human body is a complicated and integrated system that is composed of various scales of biological organization, from molecular to organismal, which will make the full rational drug design process and systems-level understanding of drug action extremely difficult
Despite the great synthetic diversity derived from the development of combinatorial chemistries and high-throughput screening methods, they have had notably small influence on the derivation of novel drugs and candidate compounds for primary optimization [83,84]

Summary

Introduction

Drug discovery is a long and extremely complicated process with a low success rate and vast capital investment. The high-throughput screening of various molecules has processed considerable development to identify major compounds with activity therapeutically against targets and pathways, the number of successfully identified molecular drugs did not significantly increase over the years [1]. The evidence shows that the human body is a complicated and integrated system that is composed of various scales of biological organization, from molecular to organismal, which will make the full rational drug design process and systems-level understanding of drug action extremely difficult. There is a pressing need to develop an innovative and integrated system-level approach to systematically and comprehensively parse the mechanism of drug action so as to deep understand the interplay between drugs and complex disease

Objectives

Methods

Findings

Conclusion