Multiple target-based pharmacophore design from active site structures.

Area of Science:

• Computational chemistry
• Medicinal chemistry
• Drug discovery

Background:

• Rational drug discovery utilizes methods like virtual high throughput screening (vHTS) and quantitative structure-activity relationships (QSAR).
• Current drug research focuses on designing multi-target drugs that bind to desired targets while avoiding undesirable ones.
• Achieving specificity and selectivity in drug design remains a significant challenge.

Purpose of the Study:

• To develop multi-target pharmacophores using computational methods and protein structures alone.
• To guide the discovery of novel inhibitors for plasmepsins with selectivity over human homologs like cathepsin D and pepsin.
• To create a computationally efficient method applicable to various target structures.

Main Methods:

• Utilizing the three-dimensional interaction profile of protein active sites.
• Identifying selective positions for functional groups (features).
• Employing molecular interaction fields, clique graphs, and inductive logic programming to identify complementary features.

Main Results:

• Designed multi-featured specific and selective pharmacophores.
• Validated the pharmacophores using known anti-plasmepsin II antimalarial compounds from ChEMBL.
• Demonstrated a computationally less intensive approach for identifying specific and selective binders.

Conclusions:

• The developed method successfully designs specific and selective multi-target pharmacophores.
• This approach aids in discovering novel inhibitors for targets like plasmepsins.
• The method is versatile and can be applied to any protein target class for simultaneous specific and selective binder discovery.