Identification of New Mycobacterium tuberculosis Proteasome Inhibitors Using a Knowledge-Based Computational Screening Approach.

Tahani M Almeleebia,Mesfer Al Shahrani,Irfan Ahmad,Mohammad Y Alshahrani,Abdullah M Alkahtani,Sana Iram,Md Jahoor Alam,Mohd Adnan Kausar,Mohd Saeed,Amir Saeed

doi:10.3390/molecules26082326

Abstract

Mycobacterium tuberculosis (Mtb) is a deadly tuberculosis (TB)-causing pathogen. The proteasome is vital to the survival of Mtb and is therefore validated as a potential target for anti-TB therapy. Mtb resistance to existing antibacterial agents has enhanced drastically, becoming a worldwide health issue. Therefore, new potential therapeutic agents need to be developed that can overcome the complications of TB. With this purpose, in the present study, 224,205 natural compounds from the ZINC database have been screened against the catalytic site of Mtb proteasome by the computational approach. The best scoring hits, ZINC3875469, ZINC4076131, and ZINC1883067, demonstrated robust interaction with Mtb proteasome with binding energy values of −7.19, −7.95, and −7.21 kcal/mol for the monomer (K-chain) and −8.05, −9.10, and −7.07 kcal/mol for the dimer (both K and L chains) of the beta subunit, which is relatively higher than that of reference compound HT1171 (−5.83 kcal/mol (monomer) and −5.97 kcal/mol (dimer)). In-depth molecular docking of top-scoring compounds with Mtb proteasome reveals that amino acid residues Thr1, Arg19, Ser20, Thr21, Gln22, Gly23, Asn24, Lys33, Gly47, Asp124, Ala126, Trp129, and Ala180 are crucial in binding. Furthermore, a molecular dynamics study showed steady-state interaction of hit compounds with Mtb proteasome. Computational prediction of physicochemical property assessment showed that these hits are non-toxic and possess good drug-likeness properties. This study proposed that these compounds could be utilized as potential inhibitors of Mtb proteasome to combat TB infection. However, there is a need for further bench work experiments for their validation as inhibitors of Mtb proteasome.

Highlights

Mycobacterium tuberculosis (Mtb) is a deadly tuberculosis (TB)-causing pathogen
The present study aimed to identify new possible hits from the natural compounds databases using in silico, state-of-the-art techniques that could serve as Mtb proteasome inhibitors to combat TB infection
Since the Mtb proteasome core particle has 14 chains in the beta subunit, all of which have the same active sites, the present study focused on chain K as a monomer, and the K and L chains as a dimer

Summary

Introduction

Mycobacterium tuberculosis (Mtb) is a deadly tuberculosis (TB)-causing pathogen. TB is a communicable disease that ranks in the world’s top 10 causes of death. Molecular Docking Lead hits were docked with Mtb proteasome (monomer; K-chain) by Autodock4.2 to determine the ligand–protein interaction and their binding affinities [23]. Grid points were fixed as 60 × 60 × 60 Å with the spacing of 0.375 Å These hits were docked with the dimer form (K and L chains) of the beta subunit of the Mtb proteasome, keeping the grid center points X, Y, and Z as 41.22, 0.60, and 32.31, respectively. Oxathiazol-2-one compounds altered the Mtb proteasome by interacting with the Thr residues of the core complex beta-subunit. In this study, the selected hits ZINC3875469, ZINC4076131, and ZINC1883067 were found to interact with Thr residues of the Mtb proteasome. TZaIbNleC23.8H75-4b6o9nd interacti−o7n.1s9between compo−u8n.0d5s and the Mtb pr2o8t.e9asome (monome2r6;.5K4-chain)

Mtb proteasome ZINC4076131

MD Simulation