Validation of Molecular Docking Programs for Virtual Screening against Dihydropteroate Synthase

Abstract

Dihydropteroate synthase (DHPS) is the target of the sulfonamide class of antibiotics and has been a validated antibacterial drug target for nearly 70 years. The sulfonamides target the p-aminobenzoic acid (pABA) binding site of DHPS and interfere with folate biosynthesis and ultimately prevent bacterial replication. However, widespread bacterial resistance to these drugs has severely limited their effectiveness. This study explores the second and more highly conserved pterin binding site of DHPS as an alternative approach to developing novel antibiotics that avoid resistance. In this study, five commonly-used docking programs, FlexX, Surflex, Glide, GOLD, and DOCK, and nine scoring functions, were evaluated for their ability to rank-order potential lead compounds for an extensive virtual screening study of the pterin binding site of B. anthracis DHPS. Their performance in ligand docking and scoring was judged by their ability to reproduce a known inhibitor conformation and to efficiently detect known active compounds seeded into three separate decoy sets. Two other metrics were used to assess performance; enrichment at 1% and 2%, and Receiver Operating Characteristic (ROC) curves. The effectiveness of post-docking relaxation prior to rescoring and consensus scoring were also evaluated. Finally, we have developed a straightforward statistical method of including the inhibition constants of the known active compounds when analyzing enrichment results to more accurately assess scoring performance, which we call the 'sum of the sum of log rank' or SSLR. Of the docking and scoring functions evaluated, Surflex with Surflex-Score and Glide with GlideScore were the best overall performers for use in virtual screening against the DHPS target, with neither combination showing statistically significant superiority over the other in enrichment studies or pose selection. Post-docking ligand relaxation and consensus scoring did not improve overall enrichment.

Challenges and advances in computational docking: 2009 in review

“…Their multiobjective optimization method (MOSFOM) simultaneously considers the energy (AMBER) and the contact score of DOCK, and was demonstrated to improve enrichment in virtual screening. Contrary to the above examples, in some studies, it has been noted that consensus scoring lead to none or only moderate improvement in docking accuracy and/or overall enrichment (71,88).…”

Docking of Potent Anticancer Agents; 4-(Pyrazol-4yl)-Pyrimidine Derivatives as Selective Cyclin-Dependent Kinase 4/6 Inhibitors

“…In this method, a compound with a known conformation and orientation from a cocrystal structure is redock into the target's active site [11]. Natural ligand of the receptor molecule CDK is ATP.…”

“…Several methods have been available and reported for validating docking programs [9], [10]. The commonly used method is pose selection, by using a cocrystal structure with aknown inhibitor [11] In this computational chemistry research, we conduct docking study on a series of 4-(pyrazol-4-yl)-pyrimidine derivatives towards its receptors, CDK4 and CDK2. We compared the docking result between three compounds; the parent compound (a), the most selective (b) and the least selective (c) compound.…”

Molecular Docking and Dynamic Simulation Studies of Benzoylated Emodin into HBV Core Protein

“…Programs that can return poses below RMSD value of 1.5 or 2 A is considered to have performed successfully. 20 Further ligands present are replaced with an emodin and benzoylated emodin by performing alignment and docking simulations performed for each of these compounds. There are six chains of HBV core protein in 5E0I which each charged with its ligand.…”