Human lactate dehydrogenase A (LDHA) is an anaerobic glycolytic enzyme involved in the inter-conversion of pyruvate to lactate. The level of LDHA in various types of cancer cells is found to be elevated and the dependence of cancer cells on anaerobic glycolysis is viewed as the reason for this elevation. Moreover, inhibition of LDHA activity has been shown to be effective in impairing the growth of tumors, making the LDHA as a potential target for cancer therapy. In this computational study, we have performed a pharmacophore based screening of approved drugs followed by a molecular docking based screening to find a few potential LDHA inhibitors. Molecular dynamics simulations have also been performed to examine the stability of the LDHA-drug complexes as obtained from the docking study. The result of the study showed that darunavir, moxalactam and eprosartan can bind to the active site of LDHA with high affinity in comparison to two known synthetic inhibitors of LDHA. The results of the molecular dynamics simulation showed that these drugs can bind stably with the enzyme through hydrogen bond and hydrophobic interactions. Hence, it is concluded that darunavir, moxalactam and eprosartan may be considered as potential inhibitors of LDHA and can be used for cancer therapy after proper validation of their effectiveness through in vitro, in vivo and clinical trials.Communicated by Ramaswamy H. Sarma.
Keywords: darunavir; drug repurposing; eprosartan; lactate dehydrogenase A; moxalactam.