InsilicoDrug Design

Abstract

In the field of computational drug design, the identification and characterisation of the biological target of interest is a major step. Despite the growing number of such resolved protein structures every year, there are still many drug targets, especially membrane proteins, for which structural determination is very difficult. In these cases, experimental knowledge on already determined bioactive molecules may be used successfully for computational ligand‐based drug‐design methods. However, for the past three decades, most drug discovery efforts have been driven by the structure of the target biomolecule. Advances in structural biology methods have provided structural information of many molecules, giving rise to the structure‐based drug‐design process as a powerful tool for drug discovery in research academia and pharmaceutical industry. Both fields in the in silico drug‐design field are commonly used, each one depending on background experimental information and relevant computational methodologies. Key Concepts The main computer‐aided drug‐design approaches are either ligand or structure based. Main ligand‐based methods for identifying bioactive compounds are chemical similarity, pharmacophore mapping and QSAR. Advances in structural biology methodologies have greatly assisted structure‐based drug design. Structure‐based methods in computational drug design are mostly molecular docking, molecular dynamics, fragment‐based drug‐design and pharmacophore modelling. Docking and pharmacophore methodologies are most commonly used for virtual screening in drug design.

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“…67 In this approach, trial compounds are docked in silico into binding sites that have been elucidated in the three-dimensional structures of the protein targets. 68 Through the implementation of physics-based equations that ground the interactions between the target and the candidate drug to quantifiable results, the binding affinities of the compounds are calculated. The compounds that present the best scores can be subsequently validated in vitro, to ascertain whether they indeed bind to the target and have the desired effects and the simultaneous absence of toxicity, both in cell cultures and in animal models.…”

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“…However, this could depend on the resolution of the X-ray structure of the protein (26). The docking depends on a variety of interactions such as electrostatics, potential hydrogen bond donors and acceptors, hydrophobic patches, van der Waals and also effected by neighboring patches near the ligand-binding sites 29,40,44 . Different types of interactions were observed between the selected molecules and BabA protein as shown in the following figure ( Figure 1 From the results above, it can be noticed that most of the molecules have an aromatic ring(s) (5 out of 7) which is in agreement with the fact that 75% of marketed drugs contain one or more aromatic rings 45,46 .…”

“…To explore that computational aid drug design (CADD) can play an important in drug design and discovery using different approaches, among these Structure-Based Drug Design (SBDD), since a lot of 3D structures are now available. SBDD is the most powerful and efficient process for accelerating drug discovery as it is specific and cost-effective 29,30 , so it has emerged as a promising tool for the drug industry to design and optimizes ligands/drugs and become as an integral part of most drug discovery 31 .…”