Virtual Screening of Cathepsin K Inhibitors Using Docking and Pharmacophore Models

Abstract

Cathepsin K is a lysosomal cysteine protease that is highly and selectively expressed in osteoclasts, the cells which degrade bone during the continuous cycle of bone degradation and formation. Inhibition of cathepsin K represents a potential therapeutic approach for diseases characterized by excessive bone resorption such as osteoporosis. In order to elucidate the essential structural features for cathepsin K, a three-dimensional pharmacophore hypotheses were built on the basis of a set of known cathepsin K inhibitors selected from the literature using catalyst program. Several methods are used in validation of pharmacophore hypothesis were presented, and the fourth hypothesis (Hypo4) was considered to be the best pharmacophore hypothesis which has a correlation coefficient of 0.944 with training set and has high prediction of activity for a set of 30 test molecules with correlation of 0.909. The model (Hypo4) was then employed as 3D search query to screen the Maybridge database containing 59,000 compounds, to discover novel and highly potent ligands. For analyzing intermolecular interactions between protein and ligand, all the molecules were docked using Glide software. The result showed that the type and spatial location of chemical features encoded in the pharmacophore are in full agreement with the enzyme inhibitor interaction pattern identified from molecular docking.

Inhibition of Osteoclast Differentiation by Ginsenoside Rg3 in RAW264.7 Cells via RANKL, JNK and p38 MAPK Pathways Through a Modulation of Cathepsin K: An In Silico and In Vitro Study

“…The analysis of our PASS results clearly indicated that Rg3 showed significant predicted biological activity including the muscle weakness treatment, metabolic disorder treatment, transcription factor inhibitor, and transcription factor stimulant (Table ). Our results are in agreement with the previous results suggesting that different natural compounds have the inhibitory effect on the expression of Cat‐K (Ravikumar et al, ). Thus, these in silico results ascertained our hypothesis that Rg3 interacted with the targeted Cat‐K protein.…”

New compounds identified through in silico approaches reduce the α-synuclein expression by inhibiting prolyl oligopeptidase in vitro

“…Pharm-B exhibited a higher enrichment factor value (29.88) than Pharm-A (26.93). Generally, the goodness of fit (GH) scores ranged from 0, which indicates a null model, to 1, which indicates an ideal model 31 . Therefore, a model with a GH score that is greater than 0.6 and closer to 1 is expected to be more reliable in the screening of large chemical databases 32 .…”

Pharmacophore-based virtual screening: a review of recent applications

“…Catalyst, a leading software for chemical featurebased pharmacophore modeling, is arguably the most widely used program. A number of previous studies focused on the validation of pharmacophore-based virtual screening -by evaluating pharmacophore models, by pharmacophore identification and by the associated methodologies for screening -with respect to the reproduction of the binding affinity or enrichment of hit lists from a database of decoys [24][25][26][27][28][29][30][31][32]. In this section, we focus on examples that have shown, to some extent, the successful application of pharmacophore-based virtual screening for new drug discovery.…”