Molecular Docking of Selective Binding Affinity of Sulfonamide Derivatives as Potential Antimalarial Agents Targeting the Glycolytic Enzymes: GAPDH, Aldolase and TPI

作     者：Neville Forlemu Porshaye Watkins Joseph Sloop 

作者机构：School of Science & Technology (Chemistry) Georgia Gwinnett College 1000 University Center Lane Lawrenceville GA USA 

出 版 物：《Open Journal of Biophysics》 (生物物理学期刊（英文）)

年 卷 期：2017年第7卷第1期

页      面：41-57页

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

主　　题：Malaria Glycolytic Enzymes AutoDock4.2 Dissociation Constant Triosephosphate Isomerase Binding Affinity 

摘      要：The parasite Plasmodium falciparum is responsible for the major world scourge malaria, a disease that affects 3.3 billion people worldwide. The development of new drugs is critical because of the diminished effectiveness of current antimalarial agents mainly due to parasitic resistance, side effects and cost. Molecular docking was used to explore structural motifs responsible for the interactions between triose phosphate isomerase (TPI), glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and aldolase (ALD) from human and Plasmodium cells with 8 novel sufonylamide derivatives. All the ligands modeled, interact with all three enzymes in the micromolar range. The top ligand (sulfaE) shows a 70-fold increase in selective binding to pfTPI compared to hTPI (dissociation constant-KI of 7.83 μM and 0.177 μM for hTPI and pfTPI respectively), on par with antimalarial drug *** and GAPDH form complexes with similar binding sites, comprising amino acids of similar chemical properties and polarities. Human TPI and pfTPI bind sulfonamide derivatives using two distinct binding sites and residues. Key residues at the dimer interface of pfTPI (VAL44, SER45, TYR48, GLN64, ASN65, VAL78) form a tight pocket with favorable polar contacts. The affinity with TPI is the most specific, stable, and selective suggesting pfTPI is a candidate for development of antimalarial drugs.