In silico insights into prediction and analysis of potential novel pyrrolopyridine analogs against human MAPKAPK-2: a new SAR-based hierarchical clustering approach

Abstract

In the present study, we have focused on to elucidate potential bioactive pyrrolopyridine (PYP23) analogs against human mitogen-activated protein kinase-activated protein kinase-2 (MK-2). Here, in silico methods and computational systems biology tools were used as rational strategies to predict novel PYP23 analogs against the MK-2. Initially, crystal structure (PDB-ID: 2P3G) consists steriochemical conflicts were rectified by structure-optimization approaches using the Modeller program, and a new optimized-high resolution model was generated. The stereochemical qualities of the predicted MK-2 model were judged; these showed that the model was reliable for docking assessments. SAR-based bioactivity analysis showed that among the 197 datasets only 15 candidates contained bioactivity data and were accepted as probable MK-2 inhibitors. Virtual screening and docking strategies of dataset compounds against the ligand-binding domain of MK-2 recognized 13 composites containing high binding affinity than known compounds. Furthermore, the comparative structure clustering, in silico toxicogenomics and QSAR-based anticancer properties prediction approaches were successful in the recognition of five best potential compounds such as 60118340, 60118338, 60117736, 60118473 and 60118322, which have great anticancer and drug-likeness with non-toxicity class indices. Leu⁷⁰, Glu¹³⁹, Leu¹⁴¹, Glu¹⁴⁵, Glu¹⁹⁰, Thr²⁰⁶ and Asp²⁰⁷ were found to be novel hotspot residues prominently involved in H-bonds framing with ligands. Interestingly, they have shown better molecular similarity with known bioactive PYP inhibitors. Thus, predicted five compounds can useful as possible chemotherapeutic agents for MK-2 and show similar molecular actions like known PYP inhibitors. Overall, these streamlined new methods may have great potential to reveal possible ligands toward other molecular targets and biomarkers.

Keywords: ADMET analysis; Ensemble docking; MAP kinase-activated protein kinase-2; Pyrrolopyrimidine inhibitors; SAR-based bioassay clustering; Virtual screening.