Modeling of human M1 aminopeptidases for in silico screening of potential Plasmodium falciparum alanine aminopeptidase (PfA-M1) specific inhibitors

Plasmodium falciparum alanine M1-aminopeptidase (PfA-M1) is a validated target for anti-malarial drug development. Presence ofsignificant similarity between PfA-M1 and human M1-aminopeptidases, particularly within regions of enzyme active site leads toproblem of non-specificity and off-target binding for known aminopeptidase inhibitors. Molecular docking based in silico screeningapproach for off-target binding has high potential but requires 3D-structure of all human M1-aminopeptidaes. Therefore, in thepresent study 3D structural models of seven human M1-aminopeptidases were developed. The robustness of docking parametersand quality of predicted human M1-aminopeptidases structural models was evaluated by stereochemical analysis and docking oftheir respective known inhibitors. The docking scores were in agreement with the inhibitory concentrations elucidated in enzymeassays of respective inhibitor enzyme combinations (r2≈0.70). Further docking analysis of fifteen potential PfA-M1 inhibitors(virtual screening identified) showed that three compounds had less docking affinity for human M1-aminopeptidases as comparedto PfA-M1. These three identified potential lead compounds can be validated with enzyme assays and used as a scaffold fordesigning of new compounds with increased specificity towards PfA-M1.