IN SILICO, DEVELOPMENT AND CHARACTERIZATION OF CILNIDIPINE ANALOGUES FOR ENHANCED SOLUBILITY AND THERAPEUTIC POTENTIAL IN THE TREATMENT OF ANGINA PECTORIS

PAVANKUMAR KROSURI; MOTHILAL MOHAN

doi:10.22159/ijap.2025v17i2.52603

Authors

PAVANKUMAR KROSURI SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu-603203, Tamilnadu, India
MOTHILAL MOHAN Department of Pharmaceutics, SRM College of Pharmacy, SRM IST, Kattankulathur, Chengalpattu-603203, Tamilnadu, India https://orcid.org/0000-0003-0451-2890

DOI:

https://doi.org/10.22159/ijap.2025v17i2.52603

Keywords:

Cilnidipine analogues, Drug discovery, Toxicity, Nanoparticles, Taguchi Design

Abstract

Objective: Angina pectoris remains a significant clinical challenge due to the limitations of current therapies, such as inadequate efficacy and undesirable side effects. This study aims to address these issues by developing a novel treatment approach based on Cilnidipine analogues and nanotechnology, focusing on the lead compound Cilnidipine Analogue (CC5; ZINC101069658).

Methods: CC5 was identified as the most promising candidate due to its optimal balance of lipophilicity, solubility, absorption, and synthetic feasibility. A bioinformatics-driven approach uncovered 60 potential target hub genes related to angina pectoris, with Protein-Protein Interaction (PPI) analysis highlighting Estimated Glomerular Filtration Rate (EGFR) as a key target. Molecular docking and Molecular Dynamics simulations confirmed the stability and strong binding affinity of CC5 with the EGFR-associated protein (5wb7). SWISSADME analysis revealed moderate lipophilicity, poor water solubility, and low gastrointestinal absorption, while HOMO-LUMO studies suggested enhanced chemical stability. The Taguchi design of experiments indicated that stirring speed was critical for nanoparticle size, and stabilizer concentration significantly impacted Encapsulation Efficiency (EE) and zeta potential.

Results: Molecular docking studies showed a strong binding affinity of-8.6 kcal/mol with EGFR, while pharmacokinetic evaluations indicated favourable absorption and moderate lipophilicity, supporting CC5’s potential as an optimized therapeutic agent for angina pectoris. CC5 nanoparticles exhibited a 2.63-fold increase in solubility compared to the parent compound. Fourier Transform Infrared Spectroscopy, Transmission Electron Microscopy, and X-ray Diffraction characterization confirmed the successful nanoparticle formulation. In vitro dissolution studies demonstrated superior drug release from CC5-loaded nanoparticulate oral disintegrating tablets, with the CAF9 (CC5 Formulation 9) showing rapid onset of action and a significantly improved release profile (98.89±1.10% at 30 min) compared to controlled (80.58%) and marketed preparations (18.85%).

Conclusion: The study demonstrates the therapeutic potential of ZINC101069658, a CC5, through its enhanced solubility and reduced Crystallinity. The lead compound was made into Nanoparticles using Pluronic F 188 as carrier. These nanoparticles were further formulated to oral disintegrating tablets for rapid drug release good stability compared to conventional tablets. These findings suggest that ZINC101069658 could be a promising candidate for the treatment of angina pectoris.

References

Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001 Mar;46(1-3):3-26. doi: 10.1016/s0169-409x(00)00129-0, PMID 11259830.

Ahmmed F, Islam AU, Mukhrish YE, Bakri YE, Ahmad S, Ozeki Y. Efficient antibacterial/antifungal activities: synthesis molecular docking molecular dynamics pharmacokinetic and binding free energy of galactopyranoside derivatives. Molecules. 2022 Dec;28(1):219. doi: 10.3390/molecules28010219, PMID 36615413.

Wang M, Yang S, Shao M, Zhang Q, Wang X, LU L. Identification of potential bioactive ingredients and mechanisms of the guanxin suhe pill on angina pectoris by integrating network pharmacology and molecular docking. Evid Based Complement Alternat Med. 2021 Aug;2021:4280482. doi: 10.1155/2021/4280482, PMID 34422068.

Hosen MA, Alam A, Islam M, Fujii Y, Ozeki Y, Kawsar SM. Geometrical optimization pass prediction molecular docking and in silico admet studies of thymidine derivatives against fimh adhesion of escherichia coli. Bulg Chem Commun. 2021 Oct;53:327-42.

Kawsar SM, Hossain MA. An optimization and pharmacokinetic studies of some thymidine derivatives. Turkish Computational and Theoretical Chemistry. 2020;4(2):59-66. doi: 10.33435/tcandtc.718807.

Choudhary MI, Begum A, Abbaskhan A, Musharraf SG, Ejaz A, Atta-ur-Rahman. Two new antioxidant phenylpropanoids from Lindelofia stylosa. Chem Biodivers. 2008 Dec;5(12):2676-83. doi: 10.1002/cbdv.200890221, PMID 19089825.

Xiao ZP, Shi DH, LI HQ, Zhang LN, XU C, Zhu HL. Polyphenols based on isoflavones as inhibitors of helicobacter pylori urease. Bioorg Med Chem. 2007 Jun;15(11):3703-10. doi: 10.1016/j.bmc.2007.03.045, PMID 17400458.

LI HQ, Xiao ZP, Yin Luo T, Yan T, LV PC, Zhu HL. Amines and oximes derived from deoxybenzoins as helicobacter pylori urease inhibitors. Eur J Med Chem. 2009 May;44(5):2246-51. doi: 10.1016/j.ejmech.2008.06.001, PMID 18625539.

Xiao ZP, Wang XD, Peng ZY, Huang S, Yang P, LI QS. Molecular docking kinetics study and structure activity relationship analysis of quercetin and its analogous as helicobacter pylori urease inhibitors. J Agric Food Chem. 2012 Oct;60(42):10572-7. doi: 10.1021/jf303393n, PMID 23067328.

Xiao ZP, Peng ZY, Dong JJ, HE J, Ouyang H, Feng YT. Synthesis structure activity relationship analysis and kinetics study of reductive derivatives of flavonoids as helicobacter pylori urease inhibitors. Eur J Med Chem. 2013 May;63:685-95. doi: 10.1016/j.ejmech.2013.03.016, PMID 23567958.

Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT. Glide: a new approach for rapid accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem. 2004 Mar;47(7):1739-49. doi: 10.1021/jm0306430, PMID 15027865.

Sareen S, Mathew G, Joseph L. Improvement in solubility of poor water soluble drugs by solid dispersion. Int J Pharm Investig. 2012 Jan;2(1):12-7. doi: 10.4103/2230-973X.96921, PMID 23071955.

Bhalani DV, Nutan B, Kumar A, Singh Chandel AK. Bioavailability enhancement techniques for poorly aqueous soluble drugs and therapeutics. Biomedicines. 2022 Aug;10(9):2055. doi: 10.3390/biomedicines10092055, PMID 36140156.

Kumari L, Choudhari Y, Patel P, Gupta GD, Singh D, Rosenholm JM. Advancement in solubilization approaches: a step towards bioavailability enhancement of poorly soluble drugs. Life (Basel). 2023 Apr;13(5):1099. doi: 10.3390/life13051099, PMID 37240744.

Khan KU, Minhas MU, Badshah SF, Suhail M, Ahmad A, Ijaz S. Overview of nanoparticulate strategies for solubility enhancement of poorly soluble drugs. Life Sci. 2022 Feb;291:120301. doi: 10.1016/j.lfs.2022.120301, PMID 34999114.

Abuzar SM, Hyun SM, Kim JH, Park HJ, Kim MS, Park JS. Enhancing the solubility and bioavailability of poorly water soluble drugs using supercritical antisolvent (SAS) process. Int J Pharm. 2018 Mar;538(1-2):1-13. doi: 10.1016/j.ijpharm.2017.12.041, PMID 29278733.

Chakraborty RN, Langade D, More S, Revandkar V, Birla A. Efficacy of cilnidipine (L/N-type calcium channel blocker) in treatment of hypertension: a meta-analysis of randomized and non randomized controlled trials. Cureus. 2021 Nov;13(11):e19822. doi: 10.7759/cureus.19822, PMID 34963839.

Wang AL, Iadecola C, Wang G. New generations of dihydropyridines for treatment of hypertension. J Geriatr Cardiol. 2017 Jan;14(1):67-72. doi: 10.11909/j.issn.1671-5411.2017.01.006, PMID 28270844.

Alviar CL, Devarapally S, Nadkarni GN, Romero J, Benjo AM, Javed F. Efficacy and safety of dual calcium channel blockade for the treatment of hypertension: a meta-analysis. Am J Hypertens. 2013 Feb;26(2):287-97. doi: 10.1093/ajh/hps009, PMID 23382415.

Tingle BI, Tang KG, Castanon M, Gutierrez JJ, Khurelbaatar M, Dandarchuluun C. Zinc-22-A free multi-billion scale database of tangible compounds for ligand discovery. J Chem Inf Model. 2023 Apr;63(4):1166-76. doi: 10.1021/acs.jcim.2c01253, PMID 36790087.

LE TT, DO PC. Molecular docking study of various enterovirus-A71 3C protease proteins and their potential inhibitors. Front Microbiol. 2022 Sep;13:987801. doi: 10.3389/fmicb.2022.987801, PMID 36246267.

Khalid Z, Shafqat SS, Ahmad HA, Munawar MA, Mutahir S, Elkholi SM. A combined experimental and computational study of novel benzotriazinone carboxamides as alpha glucosidase inhibitors. Molecules. 2023 Sep;28(18):6623. doi: 10.3390/molecules28186623, PMID 37764399.

Duran Iturbide NA, Diaz Eufracio BI, Medina Franco JL. In silico ADME/Tox profiling of natural products: a focus on biofacquim. ACS Omega. 2020 Jun;5(26):16076-84. doi: 10.1021/acsomega.0c01581, PMID 32656429.

Pires DE, Blundell TL, Ascher DB. Pkcsm: predicting small molecule pharmacokinetic and toxicity properties using graph based signatures. J Med Chem. 2015 May;58(9):4066-72. doi: 10.1021/acs.jmedchem.5b00104, PMID 25860834.

Amberger JS, Hamosh A. Searching online mendelian inheritance in man (OMIM): a knowledgebase of human genes and genetic phenotypes. Curr Protoc Bioinformatics. 2017 Jun;58:1.2.1-1.2.12. doi: 10.1002/cpbi.27, PMID 28654725.

Tanoli Z, Seemab U, Scherer A, Wennerberg K, Tang J, Vaha Koskela M. Exploration of databases and methods supporting drug repurposing: a comprehensive survey. Brief Bioinform. 2021 Feb;22(2):1656-78. doi: 10.1093/bib/bbaa003, PMID 32055842.

Trott O, Olson AJ. Auto dock vina: improving the speed and accuracy of docking with a new scoring function efficient optimization and multithreading. J Comput Chem. 2010 Feb;31(2):455-61. doi: 10.1002/jcc.21334, PMID 19499576.

Meng XY, Zhang HX, Mezei M, Cui M. Molecular docking: a powerful approach for structure based drug discovery. Curr Comput Aided Drug Des. 2011 Jun;7(2):146-57. doi: 10.2174/157340911795677602, PMID 21534921. PMCID PMC3151162.

Daina A, Michielin O, Zoete V. Swiss ADME: a free web tool to evaluate pharmacokinetics drug likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017 Mar;7:42717. doi: 10.1038/srep42717, PMID 28256516.

Mumit MA, Pal TK, Alam MA, Islam MA, Paul S, Sheikh MC. DFT studies on vibrational and electronic spectra HOMO-LUMO MEP HOMA NBO and molecular docking analysis of benzyl-3-N-(2,4,5-trimethoxyphenylmethylene) hydrazinecarbodithioate. J Mol Struct. 2020 Nov;1220:128715. doi: 10.1016/j.molstruc.2020.128715, PMID 32834109.

Budiman A, Aulifa DL. A comparative study of the pharmaceutical properties between amorphous drugs loaded mesoporous silica and pure amorphous drugs prepared by solvent evaporation. Pharmaceuticals (Basel). 2022 Jun 9;15(6):730. doi: 10.3390/ph15060730, PMID 35745649, PMCID PMC9228546.

El-Assal MI, Samuel D. Optimization of rivastigmine chitosan nanoparticles for neurodegenerative alzheimer; in vitro and ex vivo characterizations. Int J Pharm Pharm Sci. 2022 Jan;14(1):17-27. doi: 10.22159/ijpps.2022v14i1.43145.

Madan JR, Khude PA, Dua K. Development and evaluation of solid lipid nanoparticles of mometasone furoate for topical delivery. Int J Pharm Investig. 2014 Feb;4(2):60-4. doi: 10.4103/2230-973X.133047, PMID 25006550.

Kamaraj N, Rajaguru PY, Issac PK, Sundaresan S. Fabrication characterization in vitro drug release and glucose uptake activity of 14-deoxy 11, 12-didehydroandrographolide loaded polycaprolactone nanoparticles. Asian J Pharm Sci. 2017 Jul;12(4):353-62. doi: 10.1016/j.ajps.2017.02.003, PMID 32104346.

Mhetre RL, Hol VB, Chanshetti RR, Dhole SN. Optimisation of cilnidipine nanoparticles using box-behnken design: in vitro toxicity and bioavailability assessment. Materials Technology. 2022;37(11):1796-807. doi: 10.1080/10667857.2021.1988038.

Kumar JA, Bhikshapathi DV. Development of nilotinib loaded solid lipid nanoparticles and optimization by central composite design approach. Int J App Pharm. 2022 Mar;14(2):172-80. doi: 10.22159/ijap.2022v14i2.43943.

Mourdikoudis S, Pallares RM, Thanh NT. Characterization techniques for nanoparticles: comparison and complementarity upon studying nanoparticle properties. Nanoscale. 2018 Jan;10(27):12871-934. doi: 10.1039/c8nr02278j, PMID 29926865.

Nagai N, Ogata F, Kadowaki R, Deguchi S, Otake H, Nakazawa Y. Orally disintegrating tablets containing famotidine nanoparticles provide high intestinal absorbability via the energy dependent endocytosis pathway. Front Bioeng Biotechnol. 2023 Mar;11:1167291. doi: 10.3389/fbioe.2023.1167291, PMID 36970629.

Viswaja M, Bhikshapathi DV, Palanati M, Babu AK, Goje A. Formulation and evaluation of ibrutinib nanosponges incorporated tablet. Int J Appl Pharm. 2023 Mar;15(2):92-7.

Alhalaweh A, Alzghoul A, Mahlin D, Bergstrom CA. Physical stability of drugs after storage above and below the glass transition temperature: relationship to glass forming ability. Int J Pharm. 2015 Jan;495(1):312-7. doi: 10.1016/j.ijpharm.2015.08.101, PMID 26341321.

Kurian T. Molecular docking study of epigallocatechin gallate on FLT3 in complex with gilteritinib for anticancer activity. Asian J Pharm Clin Res. 2024 Jan;17(1):5-7. doi: 10.22159/ajpcr.2024.v17i1.48733.

Chakrabarti M. Revolutionizing antimicrobial drug discovery: computational design and ADMET studies of emerging potent anti-microbial agents. Int J Pharm Pharm Sci. 2023 Aug;15(8):28-35. doi: 10.22159/ijpps.2023v15i8.48526.

Aiswariya, BVS, Satya MS. Molecular docking and admet studies of benzotriazole derivatives tethered with isoniazid for antifungal activity. Int J Curr Pharm Sci. 2022;14(4):78-80. doi: 10.22159/ijcpr.2022v14i4.2004.

Pant A, Sharma G, Saini S, Kaur G, Jain A, Thakur A. QBD driven development of phospholipid embedded lipidic nanocarriers of raloxifene: extensive in vitro and in vivo evaluation studies. Drug Deliv Transl Res. 2024 Mar;14(3):730-56. doi: 10.1007/s13346-023-01427-3, PMID 37768530.

Birla D, Khandale N, Bashir B, Shahbaz Alam M, Vishwas S, Gupta G. Application of quality by design in optimization of nanoformulations: principle perspectives and practices. Drug Deliv Transl Res. 2024 Aug 10. doi: 10.1007/s13346-024-01681-z, PMID 39126576.