A holistic molecular modelling approach to design novel indole-2-carboxamide derivatives as potential inhibitors of MmpL3
Molecular Docking Simulation
0301 basic medicine
03 medical and health sciences
Indoles
Antitubercular Agents
Humans
Membrane Proteins
Quantitative Structure-Activity Relationship
Tuberculosis
Mycobacterium tuberculosis
Molecular Dynamics Simulation
3. Good health
DOI:
10.1080/1062936x.2022.2096691
Publication Date:
2022-07-19T07:44:45Z
AUTHORS (5)
ABSTRACT
Tuberculosis is an infectious air-borne disease and one of the leading causes of death globally among all infectious diseases. There is an urgent need to develop antitubercular drugs that would be highly efficient and less toxic than the presently available marketed drugs. Mycobacterium membrane protein large 3 (MmpL3) is an emerging drug target in tuberculosis with various classes of molecules that have been known to inhibit it. In this study, a dataset of indole-2-carboxamides showing antitubercular activity by inhibiting MmpL3 was utilized. Initially, a chimera-based homology model was developed and docking was performed with the filtered dataset to analyse the interactions. Thereafter, molecular dynamics simulations were run with representative molecules to gain a better insight on the binding patterns. To attain a more quantitative correlation, an atom-based 3D QSAR model was developed which complemented the results from the previous models. A library of novel indole-2-carboxamides was then generated using core hopping-based ligand enumeration and upon screening on our workflow model it predicted three molecules as potent antitubercular compounds. This work not only helps to gain new insights on the interactions at the MmpL3 binding site but also provides novel indole-2-carboxamides having the potential to become antitubercular drugs in future.
SUPPLEMENTAL MATERIAL
Coming soon ....
REFERENCES (32)
CITATIONS (2)
EXTERNAL LINKS
PlumX Metrics
RECOMMENDATIONS
FAIR ASSESSMENT
Coming soon ....
JUPYTER LAB
Coming soon ....