title: Molecular dynamics-based investigation of InhA substrate binding loop for diverse biological activity of direct InhA inhibitors.
abstract: The closed conformation of substrate binding loop (SBL) is considered significant for biological activity of direct InhA inhibitors (DIIs). However, exact interactions of SBL with inhibitors are not characterized yet to emphasize over SBL conformations. The seven InhA-DII complexes are analyzed using molecular dynamics simulation to deduce the mechanism for closed and open conformation of SBL. MMGBSA binding energy calculations and decompositions help to identify Ala198, Met199, Ile202, Val203, Ile215, and Leu218 in SBL region as the key residues. The interactions of DIIs with SBL residues particularly Ile202, Val203, Ile215, and Leu218 are found considerable for closed SBL conformation. This difference is accounted for closed state of SBL in 2X23, and open/moderately open state in other complexes. This study substantiates the loop ordering property of DIIs as the basis for high-affinity InhA inhibitors under the molecular recognition phenomena. This property can be used as a parameter to identify potential DIIs using virtual screening approaches.
authors.affiliation: a Department of Pharmacoinformatics , National Institute of Pharmaceutical Education and Research , Sector 67, S.A.S. Nagar 160 062 , Punjab , India.
authors.forename: Vivek
authors.initials: V
authors.lastname: Kumar
authors.affiliation: a Department of Pharmacoinformatics , National Institute of Pharmaceutical Education and Research , Sector 67, S.A.S. Nagar 160 062 , Punjab , India.
authors.forename: M Elizabeth
authors.initials: ME
authors.lastname: Sobhia
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D008024:Ligands; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium
keywords: InhA; binding free energy; crystal structure; direct InhA inhibitors; substrate binding loop