Pharmmaker

Pharmmaker performs pharmacophore modeling and virtual screening to identify ligand-binding hotspots and prioritize small-molecule hits from molecular dynamics simulations containing drug-like probe molecules as part of the ProDy API.

Key Features:

• Druggability Simulations: Performs molecular dynamics simulations of target proteins in solutions containing drug-like probe molecules to assess binding potential.
• Identification and Analysis of High Affinity Residues: Identifies high-affinity residues for each probe type and selects hot spots proximal to sites identified by DruGUI (a ProDy module).
• Interaction Ranking: Ranks interactions between identified high-affinity residues and specific probes to prioritize binding poses and protein conformations.
• Snapshot Collection and Pharmacophore Model Construction: Collects top-ranked simulation snapshots to extract probe binding poses and corresponding protein conformations and constructs pharmacophore models (PMs).
• Virtual Screening Integration: Applies constructed pharmacophore models as filters in structure-based virtual screening to identify hits in small-molecule libraries.

Scientific Applications:

• Computer-aided Drug Discovery (CADD): Supports identification and prioritization of potential drug candidates by simulating and analyzing protein–ligand interactions.
• Structure-based Virtual Screening: Uses pharmacophore models derived from MD snapshots to filter and rank compounds from small-molecule libraries.

Methodology:

Performs druggability molecular dynamics simulations with drug-like probe molecules, identifies high-affinity residues and hot spots (including those near DruGUI-identified sites), ranks probe–residue interactions, collects top-ranked snapshots to obtain probe binding poses and protein conformations, and constructs pharmacophore models used in structure-based virtual screening.