Alchemical Grid Dock (AlGDock) calculations in the D3R Grand Challenge 3

Abstract

We participated in Subchallenges 1 and 2 of the Drug Design Data Resource (D3R) Grand Challenge 3. To prepare our submissions, we performed molecular docking with UCSF DOCK 6 and binding potential of mean force (BPMF) calculations-free energy calculations between flexible ligands and rigid receptors-using our open-source software package Alchemical Grid Dock (AlGDock). For each system, submissions were based on the minimum BPMF calculated for a selected set of crystal structures. In Subchallenge 1, our workflow performed poorly. Possible reasons for the poor performance include the neglect of cooperative ligands and limited sampling of ligand binding poses. In Subchallenge 2, our workflow led to some of most highly correlated submissions (Pearson R = 0.5) for vascular endothelial growth factor receptor 2. However, our results were poorly correlated for Janus Kinase 2 and Mitogen-activated protein kinase 14. Affinity prediction could potentially be improved by systematic selection of more diverse receptor configurations.

Docking rigid macrocycles using Convex-PL, AutoDock Vina, and RDKit in the D3R Grand Challenge 4

“…The two lat-115 est Grand Challenges are also remarkable for the first 116 demonstrations of the 3D convolutional neural network-117 based methods [15]. Other approaches included molec-118 ular dynamics-based sampling and thermodynamic av-119 eraging [16] and implicit ligand theory [17] for binding 120 free energy predictions.…”

Alchemical Grid Dock (AlGDock): Binding Free Energy Calculations between Flexible Ligands and Rigid Receptors

“…Results from our purely physics-based approach were competitive with methods using knowledge-based potentials, which were the best performers in the challenge. As discussed in Xie and Minh 8 , several issues led to weaker performance in other subchallenges, including the neglect of DMSO and SO 4 in the binding site of Cathepsin S and poor selection of receptor snapshots for free energy calculations with Janus Kinase 2…”