Exploring 3D-QSAR Studies To Identify Potential Small Molecule for Treating Alzheimer Disease: A Case Study with Beta-Secretase Inhibitors

Uttam A More; Maitri  Patel; Krishna  Patel; Harsiddhi  Patel; Kruti Y Patel; Neha  Jain; Shabeena  Khan; Kinjal  Vasandiya; Malleshappa N Noolvi; Mahesh B Palkar

doi:10.5937/scriptamed56-55829

Uttam A More Shree Dhanvantary Pharmacy College
Maitri Patel Department of Pharmaceutical Chemistry, Shree Dhanvantary Pharmacy College, Kim-394110, Gujarat, India https://orcid.org/0009-0003-9430-9331
Krishna Patel Department of Pharmaceutical Chemistry, Shree Dhanvantary Pharmacy College, Kim-394110, Gujarat, India https://orcid.org/0009-0003-9430-9331
Harsiddhi Patel Department of Pharmaceutical Chemistry, Shree Dhanvantary Pharmacy College, Kim-394110, Gujarat, India https://orcid.org/0009-0006-9559-1713
Kruti Y Patel Department of Pharmaceutical Chemistry, Shree Dhanvantary Pharmacy College, Kim-394110, Gujarat, India https://orcid.org/0009-0006-6792-8446
Neha Jain Department of Pharmaceutics, Shree Dhanvantary Pharmacy College, Kim-394110, Gujarat, India https://orcid.org/0009-0001-0496-9674
Shabeena Khan Department of Pharmaceutical Chemistry, Shree Dhanvantary Pharmacy College, Kim-394110, Gujarat, India https://orcid.org/0009-0001-7707-6260
Kinjal Vasandiya Department of Pharmaceutical Chemistry, Shree Dhanvantary Pharmacy College, Kim-394110, Gujarat, India https://orcid.org/0009-0008-3482-3052
Malleshappa N Noolvi Department of Pharmaceutical Chemistry, Shree Dhanvantary Pharmacy College, Kim-394110, Gujarat, India https://orcid.org/0000-0003-0497-6601
Mahesh B Palkar Department of Pharmaceutical Chemistry, Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management SVKM’s Narsee Monjee Institute of Management Studies University (NMIMS), Vile Parle (W), Mumbai, 400 056, Maharashtra, India https://orcid.org/0000-0001-7486-5275

DOI: https://doi.org/10.5937/scriptamed56-55829

Keywords: Alzheimer disease, Pharmaceutical preparations, Quantitative structure-activity relationship, Amyloid precursor protein secretases, antagonists and inhibitors, Guanidine

Abstract

Background/Aim: One of the most common neurological conditions that results in dementia is Alzheimer disease. The current treatment options for Alzheimer disease include acetylcholinesterase (AChE) and -methyl-D-aspartate (NMDA) inhibitors, but there is a significant need for further research. There are numerous molecular targets that can be used to treat Alzheimer disease. Aim of this study was to analyse beta-secretase as a target because of its documented involvement in the pathophysiology of the illness. Additionally, prior research investigated the possible therapeutic effects of derivatives based on guanidine.

Methods: A total of 146 well-known beta-secretase inhibitors were collected from various literature sources. To forecast these compounds' inhibitory potency, models were created using ligand-based drug design (LBDD) and Quantitative Structure-Activity Relationship(3D-QSAR) investigations. Six models were generated and based on the statistical parameters q² (cross-validated R²) and standard error of estimate (SEE), the 6th model was selected for further investigation.

Results: A cross-validated R² (R²cv) value of 0.764 was obtained utilising the leave-one-out (LOO) method in the partial least squares (PLS) analysis for atom-based QSAR. With an F ratio of 337.2, a SEE of 0.2306 and an R² value of 0.9516, the non-cross-validated analysis produced these results. Field-based QSAR had an R²cv value of 0.7353, while the non-cross-validated analysis produced an F ratio of 283.1, an R² value of 0.9428 and a SEE of 0.2505. Predicting the inhibitory potency of novel compounds against beta-secretase was done using the contour map analysis. Atom-based and field-based 3D-QSAR models projected the pIC₅₀ value of the proposed compound P1 to be 8.41 and 8.32, respectively.

Conclusion: The findings of this study provide valuable insights into the design of new molecules targeting beta-secretase in Alzheimer disease. The predictive models and the newly designed molecules, particularly molecule P1, could serve as potential leads for the development of new chemical entities as anti-Alzheimer agents. These results may significantly contribute to the ongoing efforts to develop more effective treatments for Alzheimer disease.

References

Blennow K, de Leon MJ, Zetterberg H. Alzheimer's disease. Lancet. 2006;368(9533):387-403. doi: 10.1016/S0140-6736(06)69113-7.

2023 Alzheimer's disease facts and figures. Alzheimer Dement. 2023;19(4):1598-695. doi: 10.1002/alz.13016.

Vassar RJ. EC‐01‐03: Bace1, The beta‐secretase enzyme: a leading therapeutic target for Alzheimer's disease. Alzheimer Dement. 2016;12:P162-P62. doi: 10.1016/j.jalz.2016.06.289.

Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002;297(5580):353-6. doi: 10.1126/science.1072994.

Menting KW, Claassen JAHR. β-secretase inhibitor; a promising novel therapeutic drug in Alzheimer’s disease. Front Aging Neurosci. 2014;6:165. doi: 10.3389/fnagi.2014.00165.

Dislich B, Lichtenthaler SF. The membrane-bound aspartyl protease BACE1: molecular and functional properties in Alzheimer’s disease and beyond. Front Physiol. 2012;3:8. doi: 10.3389/fphys.2012.00008.

Vassar R, Kovacs DM, Yan R, Wong PC. The β-secretase enzyme BACE in health and Alzheimer's disease: regulation, cell biology, function, and therapeutic potential. J Neurosci. 2009;29(41):12787-94. doi: 10.1523/JNEUROSCI.3657-09.2009.

Steiner H, Winkler E, Haass C. Chemical cross-linking provides a model of the gamma-secretase complex subunit architecture and evidence for close proximity of the C-terminal fragment of presenilin with APH-1. J Biol Chem. 2008 Dec 12;283(50):34677-86. doi: 10.1074/jbc.M709067200.

Patel S, Vuillard L, Cleasby A, Murray CW, Yon J. Apo and inhibitor complex structures of BACE (β-secretase). J Mol Biol. 2004;343(2):407-16. doi: 10.1016/j.jmb.2004.08.018.

Hong L, Tang J. Flap position of free memapsin 2 (β-secretase), a model for flap opening in aspartic protease catalysis. Biochem. 2004;43(16):4689-95. doi: 10.1021/bi0498252.

Hong L, Turner RT, Koelsch G, Shin D, Ghosh AK, Tang J. Crystal structure of memapsin 2 (β-secretase) in complex with an inhibitor OM00-3. Biochem. 2002;41(36):10963-67. doi: 10.1021/bi026232n.

Hong L, Koelsch G, Lin X, Wu S, Terzyan S, Ghosh AK, et al. Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science. 2000 Oct 6;290(5489):150-3. doi: 10.1126/science.290.5489.150.

Kim KH. Comparative molecular field analysis (CoMFA). In: Dean PM, ed. Molecular similarity in drug design. Dordrecht: Springer Netherlands, 1995; pp. 291-331. doi: 10.1007/978-94-011-1350-2_12.

Klebe G. Comparative molecular similarity indices analysis: CoMSIA. Persp Drug Discovery Design 1998;12(0):87-104 doi: 10.1023/A:1017025803403.

Kalva S, Vinod D, Saleena LM. Field-and Gaussian-based 3D-QSAR studies on barbiturate analogs as MMP-9 inhibitors. Med Chem Res. 2013;22:5303-13. doi: 10.1007/s00044-013-0479-6..

Klebe G. Quantitative Structure–Activity Relationships. In: Klebe G, ed. Drug design: methodology, concepts, and mode-of-action. Berlin, Heidelberg: Springer Berlin Heidelberg, 2013; pp. 371-96. doi: 10.1007/978-3-642-17907-5_18.

Wesnak N, Bhat SS, Romero AH. Structural exploration of low-energy Lennard–Jones–Gauss clusters with a genetic algorithm. Eur Physical J B. 2023;96(11):154. doi: 10.1140/epjb/s10051-023-00611-1.

Kumar SPJ, Susmita C, Sripathy KV, Agarwal DK, Pal G, Singh AN, et al. Molecular characterization and genetic diversity studies of Indian soybean (Glycine max (L.) Merr.) cultivars using SSR markers. Mol Biol Rep. 2022 Mar;49(3):2129-40. doi: 10.1007/s11033-021-07030-4.

Schrödinger LLC. Schrödinger Release 2017-1: Maestro. New York: Schrödinger LLC 2017.

Varpe BD, Jadhav SB, Chatale BC, Mali AS, Jadhav SY, Kulkarni AA. 3D-QSAR and Pharmacophore modeling of 3, 5-disubstituted indole derivatives as Pim kinase inhibitors. Struct Chem. 2020;31:1675-90. doi: 10.1007/s11224-020-01503-1.

Kharb R, Sharma PC, Yar MS. Pharmacological significance of triazole scaffold. J Enzyme Inhib Med Chem. 2011 Feb;26(1):1-21. doi: 10.3109/14756360903524304.