WITHDRAWN: Mechanistic modelling of Mycobacterium Tuberculosis beta carbonic anhydrase 3 inhibitors

Abstract

This study in particular demonstrates a novel bioinformatics pipeline to highlight the physiological and biochemical mechanism of β-CA3, a β-carbonic anhydrase encoded by Mycobacterium tuberculosis (Mtb) of Rv3273, which possesses a unique two-domain structure, with a sulfate transporter domain at the N-terminal and β-CA domain at the C-terminal. We initiated the study by constructing the 3D protein structure of β-CA3 from its sequence with the aid of homology modeling. To thoroughly investigate the essential properties of β-CA3, we further conducted computational genome sequencing, and proteomic analysis strategies to uncover the key biological and structural insights. Construction and development of a Python-based custom web server, SEQEclipse (https://seqeclipse.streamlit.app/) equipped with basic biopython work packages was done to study and gain insights into the sequence structure-function relationship of β-CA3 through analysis of its physicochemical properties, identification of phosphorylated sites and disordered regions, determination of functional class of the sequence, BLAST and MSA analysis, protein-protein interaction mechanism, and ab initio modeling strategy. We also employed a quantitative structural activity relationship (QSAR) model to understand the inhibition mechanism of small molecule modulators of β-CA3 concerning their diverse physiochemical properties. We further extended the QSAR strategy to a mechanistic system biology approach to unravel the key biological processes and metabolic pathways associated with the top β-CA3 modulators and their underlying mechanism of action to halt the pathogenesis cycle of Mtb. Our overall study outlines the biological significance of β-CA3 functionality along with a mechanistic understanding of designing small molecule modulators as anti-TB drugs for future prospectives.