Andrographolide Derivative as Therapeutic Lead Against Mutated β‐Lactamase Enzyme: An In‐Silico Approach to Combat AMR

Abstract The β‐lactamase (BlaC) enzyme is responsible for causing resistance in bacteria via inactivating β‐lactam antibiotics and thus contributes to a major role in anti‐microbial resistance (AMR). To address BlaC‐associated issues, this work presents a systematic cheminformatics analysis of andrographolide derivatives to identify the potential lead molecules against both BlaC and mutated‐BlaC (m‐BlaC) proteins to address the AMR issues. A sequential cheminformatics approach is employed by utilizing virtual‐screening, molecular‐docking, ADMET‐profiling, MD‐simulations, PCA‐analysis, FEL‐analysis, MM‐GBSA, and DFT‐analysis. The molecular‐docking and MD‐simulation analysis reveal that the compound PubChem‐ID:11624798 exhibits excellent binding affinity via hydrogen bonding with stable complex formation with both proteins. The toxicity analysis predicts class‐four toxicity for the compound, along with promising pharmacokinetic properties. DFT and MEP analysis also establishes good reactivity and stability of the compound, thus corroborating the interactive analysis between the hit compound and both proteins. Finally, the MM‐GBSA analysis revealed that the hit compound showed ∼2‐fold (m‐BlaC) and ∼20‐fold (BlaC) enhanced binding free energy when compared to control TSL. The implications of these findings suggest that the lead compound‐11624798 would potentially serve as a highly effective natural drug candidate for the management of AMR and should be explored through in‐vitro and in‐vivo assessments in the foreseeable future.