Bairagya Hridoy R, Tasneem Alvea, Rai Gyan Prakash, Reyaz Saima
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
Department of Computer Science, Jamia Millia Islamia, Jamia Nagar, Okhla, New Delhi 110025, India.
J Phys Chem B. 2021 Feb 11;125(5):1351-1362. doi: 10.1021/acs.jpcb.0c08818. Epub 2020 Dec 28.
Human guanosine monophosphate reductase (hGMPR) enzyme maintains the intracellular balance between adenine and guanine nucleotide pools, and it is an excellent target for the design of isoform-specific antileukemic agents. In the present study, we have investigated solvation properties of substrate GMP or product inosine-5'-monophosphate (IMP)-binding pocket of hGMPR by employing molecular dynamics simulations on conformations A (substrate GMP), B [substrate GMP with cofactor nicotinamide adenine dinucleotide phosphate (NDP)], C (product IMP with cofactor NDP), and D (product IMP). Nineteen water sites are identified precisely; they are responsible for the catalytic activity of this site, control structural and dynamical integrity, and electronic consequences of GMP or IMP in the binding site of hGMPR. The water sites of category-1 (W1, W4, W5, W6, W13, and W15) in normal protein and category-2 (W2, W3, W7, W8, W10, W17, and W18) in cancerous protein are unique and stabilize the guanosine or inosine group of GMP or IMP for participation in the enzymatic reaction, whereas the remaining water centers either stabilize pentose sugar ribose or the phosphate group of GMP or IMP. Furthermore, water sites of category-4 (W11, W14, and W16) appear to be conserved in all conformations during the entire simulation. The GMP-binding site in cancerous protein 2C6Q is significantly expanded, and its dynamics are very different from normal protein 2BLE. Furthermore, unique interactions of GMP(N1)···W2···Asp129/Asn158, IMP(N1)···W3···Glu289, and IMP(O6)···W10···Ser270 might be used in a water mimic drug design for hGMPR-II. In this context, water finding probability, relative interaction energy () associated with water site W, entropy, and topologies of these three water sites are thermodynamically acceptable for the water displacement method by the modified ligand. Hence, their positions in the catalytic pocket may also facilitate future drug discovery for chronic myelogenous leukemia by the design of appropriately oriented chemical groups that may displace these water molecules to mimic their structural, electronic, and thermodynamic properties.
人鸟苷单磷酸还原酶（hGMPR）维持腺嘌呤和鸟嘌呤核苷酸池之间的细胞内平衡，是设计亚型特异性抗白血病药物的理想靶点。在本研究中，我们通过对构象A（底物GMP）、B [底物GMP与辅因子烟酰胺腺嘌呤二核苷酸磷酸（NDP）]、C（产物肌苷-5'-单磷酸（IMP）与辅因子NDP）和D（产物IMP）进行分子动力学模拟，研究了hGMPR底物GMP或产物IMP结合口袋的溶剂化性质。精确识别了19个水位点；它们负责该位点的催化活性，控制hGMPR结合位点中GMP或IMP的结构和动力学完整性以及电子效应。正常蛋白中的1类水位点（W1、W4、W5、W6、W13和W15）和癌蛋白中的2类水位点（W2、W3、W7、W8、W10、W17和W18）是独特的，可稳定GMP或IMP的鸟苷或肌苷基团以参与酶促反应，而其余水中心则稳定戊糖核糖或GMP或IMP的磷酸基团。此外，在整个模拟过程中，4类水位点（W11、W14和W16）在所有构象中似乎都是保守的。癌蛋白2C6Q中的GMP结合位点显著扩大，其动力学与正常蛋白2BLE非常不同。此外，GMP（N1）···W2···Asp129/Asn158、IMP（N1）···W3···Glu289和IMP（O6）···W10···Ser270的独特相互作用可用于hGMPR-II的水模拟药物设计。在这种情况下，水发现概率、与水位点W相关的相对相互作用能（）、熵以及这三个水位点的拓扑结构对于改良配体的水置换方法在热力学上是可接受的。因此，它们在催化口袋中的位置也可能通过设计适当取向的化学基团来促进未来慢性粒细胞白血病的药物发现，这些化学基团可能取代这些水分子以模拟它们的结构、电子和热力学性质。
