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

Molecules

MohdAdnan Kausar¹  Mohd Saeed²  MdJahoor Alam²  MohammadY. Alshahrani³  MesferAl Shahrani³  Irfan Ahmad³  Amir Saeed⁴  TahaniM. Almeleebia⁵  Sana Iram⁶  AbdullahM. Alkahtani⁷ 

[1] Department of Biochemistry, College of Medicine, University of Hail, Hail 2240, Saudi Arabia;Department of Biology, College of Sciences, University of Hail, Hail 2240, Saudi Arabia;Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha 61421, Saudi Arabia;Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, University of Hail, Hail 2240, Saudi Arabia;Department of Clinical Pharmacy, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia;Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Korea;Department of Microbiology and Clinical Parasitology, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia;

关键词: Mycobacterium tuberculosis;    tuberculosis;    proteasome;    natural compounds;   

DOI  :  10.3390/molecules26082326

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown