Author(s):

Jagbir Singh, Rani Mansuri, Pravin Kumar Atul, Mahesh Kumar and Arun Sharma

Abstract: The chemo informatics and simulation approaches are highly preferred to develop drug candidate, applied in the study to develop a combinatorial library to meet, the need of new potent antimalarial. Combinatorial library was developed based on information of competitive inhibitors of Plasmodium falciparum phosphoethanolamine methyltransferase essential for membrane development for rapid multiplication of parasite. Combinatorial library was developed using LeadGrow (vLifeMDS4.6 software) by replacing the substitution sites (R1 and R2) with different aromatic and hetero-aromatic rings, and R3 with Oxygen and Sulfur. Library was screened based on druglike properties, ADMET using Discovery Studio 3.2 and also binding affinity from Schrodinger v9.6. The best scored analogs were got synthesized for in vitro testing. The thermodynamic stability was studied through dynamic simulation using Desmond. Among the druglike analogs aromatic (benzoic acid) ring at R1interacted through one hydrogen bond acceptor and donor. At position R2 hetero aromatic rings (Pyrimidine, Pyrazine and Imidazole) containing two hetero atoms could score better, actively participated in non-covalent interactions within the binding site. All the synthesized three analogs showed Schizonticidal and gametocidal activity but Comp.1 could show better IC₅₀ 3.4 µM and LD₅₀ 192.91µM with ten folds higher (56.73) selectivity index. Comp.1 inhibited protein with EC₅₀ 2.1 µM was also found thermodynamically stable till 30ns.The Comp.1 has better affinity and drug-score as well; it may have the possibilities of potent antimalarial. In-vitro observations and the thermodynamic stability of Comp.1inhibitor also established the target (PfPMT) specificity. Hence; theComp.1 may further be optimized and validated for being potent antimalarial candidate. Identified Comp.1 and other two analogs may also further be served as lead for further rational drug designing for more potent antimalarial.

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