Target-based virtual screening and molecular dynamics approach to identify potential antileishmanial agents through targeting UvrD-like helicase ATP-binding domain

Misbahuddin M Rafeeq, Nawal Helmi, Ziaullah M Sain, Johar Iqbal, Abdulrahman Alzahrani, Mohammad Othman Alkurbi, Abdullah F. Shater, Bassam M. Al-ahmadi, Mohammad Zubair Alam, Qamre Alam

Abstract


Background: About 0.7-1.0 million people worldwide have been suffering from Leishmaniasis. It falls under a neglected tropical disease (NTD) and is transmitted by biting infected female phlebotomine sandflies. The implication of “the NTD road map: together towards 2030” in the infection-prone regions worldwide has curtailed morbidity to a greater extent. However, limited options in antileishmanial oral and topical drugs must decipher more therapeutically efficacious agents to cure and eradicate the disease. 

Methods: Virtual screening based on structure, docking, & molecular dynamics approaches were adopted to identify potential lead molecules against UvrD-like helicase of Leishmania donovani from the MCULE database. Lipinski rule of five, N/O atoms (1-15), number of rings (1-2), HBDs (4-5), and HBAs (5-10) were applied as initial filters of SBVS. AutoDock Vina and GROMACS packages were used for docking and MD simulations, respectively. 

Results: Initial filters of SBVS workflow yielded 93885 ligand hits out of 100 plus million investigational ligands. Following the toxicology test, 28 ligands were gotten that were additional reduced to molecules (17) when accepted done the BOILED Egg model of the ADME. Six molecules were shortlisted with zero violation compliance of drug-likeness further than Lipinski RO5 viz., Egan, Veber, Muegge, Ghose, & bioavailability score having ΔG (-6.7 to -7.4 kcalmol-1) lesser than reference inhibitor miltefosine (-4.9 kcalmol-1). The stability of MCULE-5754880195-0-2 was found to be greater than the known inhibitor and ligand molecules mentioned above.

Conclusion:  MCULE-5754880195-0-2 has all therapeutic features by way of an admirable oral drug molecule & could be encouraging in Leishmaniasis prevention & treatment.

Keywords: UvrD-like helicase; ADME; Leishmaniasis; MCULE database; SBVS; Docking; BOILED Egg; MD simulation; ATP-binding domain 


Full Text:

PDF

References


Mishra R, Rohatgi I. (2021). Leishmaniasis. Indian Journal of Critical Care Medicine, (2021); 25(S2):S166-70.

Van Griensven J, Diro E. Visceral Leishmaniasis. Infectious Disease Clinics of North America, (2019); 33(1):79-99.

Abadías-Granado I, Diago A, Cerro PA, Palma-Ruiz AM, Gilaberte Y. Leishmaniasis cutánea y mucocutánea. Actas Dermosifiliog, (2021); 112(7): 601-18.

Mann S, Frasca K, Scherrer S, Henao-Martínez AF, Newman S, Ramanan P, et al. A Review of Leishmaniasis: Current Knowledge and Future Directions. Current Tropical Medicine Reports, (2021); 8(2):121-32.

Omondi ZN, Arserim SK, Töz S, Özbel Y. Host–Parasite Interactions: Regulation of Leishmania Infection in Sand Fly. Acta Parasitologica, (2022); 67(2):606-18.

Maksoud S, Ortega JT, Hidalgo M, Rangel HR. Leishmania donovani and HIV co-infection in vitro: Identification and characterization of main molecular players. Acta Tropica, (2022); 228:106248.

Word Health Organization. Ending the neglect to attain the Sustainable Development Goals: a road map for neglected tropical diseases 2021-2030. Geneva: World Health Organization. Word Heal

Organ, (2020);196.

Scott P, Novais FO. Cutaneous leishmaniasis: immune responses in protection and pathogenesis. Nature Reviews Immunology, (2016); 16(9):581-92.

Dorlo TPC, van Thiel PPAM, Huitema ADR, Keizer RJ, de Vries HJC, Beijnen JH, et al. Pharmacokinetics of Miltefosine in Old World Cutaneous Leishmaniasis Patients. Antimicrobial Agents and Chemotherapy, (2008); 52(8):2855-60.

Monge-Maillo B, Lopez-Velez R. Miltefosine for Visceral and Cutaneous Leishmaniasis: Drug Characteristics and Evidence-Based Treatment Recommendations. Clinical Infectious Diseases, (2015); 60(9): 1398-404.

Ajijur R, Salman A, Ahmad KMK. Combinatorial Design to Decipher Novel Lead Molecule against Mycobacterium tuberculosis. Biointerface Research in Applied Chemistry, (2021); 11(5):12993-3004.

Khan MKA, Pokharkar NB, Al-Khodairy FM, Al-Marshad FM, Arif JM. Structural Perspective on Molecular Interaction of IgG and IgA with Spike and Envelope Proteins of SARS-CoV-2 and Its Implications to Non-Specific Immunity. Biointerface Research in Applied Chemistry, (2020); 11(3):10923-39.

Khan MKA, Ahmad S, Rabbani G, Shahab U, Khan MS. Target‐based virtual screening, computational multiscoring docking and molecular dynamics simulation of small molecules as promising drug candidate affecting kinesin‐like protein KIFC1. Cell Biochemistry & Function, (2022); 40(5):451-472.

Benkert P, Biasini M, Schwede T. Toward the estimation of the absolute quality of individual protein structure models. Bioinformatics, (2011); 27(3):343-50.

Alwabli AS. Lead Identification against 3C-like Protease of SARS-CoV-2 Via Target-based Virtual Screening and Molecular Dynamics Simulation. Journal of Young Pharmacists, (2022); 14(2):179-86.

Subramanya HS, Bird LE, Brannigan JA, Wigley DB. Crystal structure of a DExx box DNA helicase. Nature (1996); 384(6607):379-83.

Studer G, Rempfer C, Waterhouse AM, Gumienny R, Haas J, Schwede T. QMEANDisCo-distance constraints applied on model quality estimation. Elofsson A, editor. Bioinformatics, (2020); 36(6):1765-71.

Brooks BR, Bruccoleri RE, Olafson BD, States DJ, Swaminathan S, Karplus M. CHARMM: A program for macromolecular energy, minimization, and dynamics calculations. Journal of Computational Chemistry, (1983); 4(2):187-217.

Ahmad KMK, Salman A, Al-Khodairy Salman F, Al-Marshad Feras M, Alshahrani Abdulrahman M, Arif Jamal M. Computational Exploration of Dibenzo [a,l] Pyrene Interaction to DNA and its Bases: Possible Implications to Human Health. Biointerface Research in Applied Chemistry, (2020); 11(4):11272-83.

Kiss R, Sandor M, Szalai FA. A public web service for drug discovery. Journal of Cheminformatics, (2012); 4(S1):P17.

Shakil S. Molecular interaction of investigational ligands with human brain acetylcholinesterase. Journal of Cellular Biochemistry, (2019);120(7):11820-30.

Ware JM, O’Connell EM, Brown T, Wetzler L, Talaat KR, Nutman TB, et al. Efficacy and Tolerability of Miltefosine in the Treatment of Cutaneous Leishmaniasis. Clinical Infectious Diseases, (2021);73(7):e2457-562.

Castro M del M, Gomez MA, Kip AE, Cossio A, Ortiz E, Navas A, et al. Pharmacokinetics of Miltefosine in Children and Adults with Cutaneous Leishmaniasis. Antimicrobial Agents and Chemotherapy, (2017); 61(3): e02198-16.

Brooks BR, Brooks CL, Mackerell AD, Nilsson L, Petrella RJ, Roux B, et al. (2009). CHARMM: The biomolecular simulation program. Journal of Computational Chemistry, (2009); 30(10):1545-614.

OLEG TROTT AJO, Schroer A. AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading. Journal of Computational Chemistry, (2010); 31(16):2967-70.

Khan MKA, Akhtar S, Arif JM. Development of In Silico Protocols to Predict Structural Insights into the Metabolic Activation Pathways of Xenobiotics. Interdisciplinary Sciences: Computational Life Sciences, (2018;10(2):329-45.

Khan MKA, Akhtar S, Arif JM. (2018). Structural Insight into the Mechanism of Dibenzo[a,l]pyrene and Benzo[a]pyrene-Mediated Cell Proliferation Using Molecular Docking Simulations. Interdisciplinary Sciences: Computational Life Sciences, (2018); 10(4):653-73.

Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports, (2017); 7(1):42717.

Attique S, Hassan M, Usman M, Atif R, Mahboob S, Al-Ghanim K, et al. A Molecular Docking Approach to Evaluate the Pharmacological Properties of Natural and Synthetic Treatment Candidates for Use against Hypertension. International Journal of Environmental Research and Public Health, (2019); 16(6):923.

Egan WJ, Merz, KM, Baldwin JJ. Prediction of Drug Absorption Using Multivariate Statistics. Journal of Medicinal Chemistry, (2000), 43(21):3867-77.

Egan WJ, Lauri G. Prediction of intestinal permeability. Advanced Drug Delivery Reviews (2002); 54(3):273-89.

Baell JB, Holloway GA. New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays. Journal of Medicinal Chemistry,(2010); 53(7):2719-40.

Brenk R, Schipani A, James D, Krasowski A, Gilbert IH, Frearson J, et al. Lessons Learnt from Assembling Screening Libraries for Drug Discovery for Neglected Diseases. ChemMedChem, (2008); 3(3):435-44.

Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJC. GROMACS: Fast, flexible, and free. Journal of Computational Chemistry, (2005); 26(16):1701-18.

Vanommeslaeghe K, MacKerell AD. Automation of the CHARMM General Force Field (CGenFF) I: Bond Perception and Atom Typing. Journal of Chemical Information and Modeling, (2012); 52(12):3144-

Vanommeslaeghe K, Hatcher E, Acharya C, Kundu S, Zhong S, Shim J, et al. CHARMM general force field: A force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields. Journal of Computational Chemistry, (2010); 31(4):671-90.

Petersen HG. Accuracy and efficiency of the particle mesh Ewald method. Journal of Chemical Physics, (1995); 103(9):3668-79.

Stenberg S, Stenqvist B. An Exact Ewald Summation Method in Theory and Practice. Journal of Physical Chemistry,(2020); 124(19):3943-6.

Fischer NM, van Maaren PJ, Ditz JC, Yildirim A, van der Spoel D. Properties of Organic Liquids when Simulated with Long-Range Lennard-Jones Interactions. Journal of Chemical Theory and Computation, (2015); 11(7):2938-44.

Laskowski RA, MacArthur MW, Moss DS, Thornton JM. PROCHECK: a program to check the stereochemical quality of protein structures. Journal of Applied Crystallography, (1993); 26(2):283-91.

Şahin S, Dege N. A newly synthesized small molecule: the evaluation against Alzheimer’s Disease by in silico drug design and computational structure analysis methods. Journal of Molecular Structure, (2021); 1236(1):130337.

Ghose AK, Viswanadhan VN, Wendoloski JJ. A Knowledge-Based Approach in Designing Combinatorial or Medicinal Chemistry Libraries for Drug Discovery. 1. A Qualitative and Quantitative Characterization of Known Drug Databases. Journal of Combinatorial Chemistry, (1999); 1(1):55-68.

Veber DF, Johnson SR, Cheng H-Y, Smith BR, Ward KW, Kopple KD. Molecular Properties That Influence the Oral Bioavailability of Drug Candidates. Journal of Medicinal Chemistry, (2002); 45(12):2615-23.

Muegge I, Heald SL, Brittelli D. Simple Selection Criteria for Drug-like Chemical Matter. Journal of Medicinal Chemistry,(2001); 44(12):1841-6.

Martin YC. A Bioavailability Score. ournal of Medicinal Chemistry, (2005); 48(9):3164-70.

Kausar MA, Shahid S, Anwar S, Kuddus M, Khan MKA, Alotaibi AD, et al. Identifying Natural Therapeutics against Diabetes via Inhibition of Dipeptidyl Peptidase 4: Molecular Docking and MD Simulation Study. Indian Journal of Pharmaceutical Education and Research, (2022); 56(1s):s21-31.

Kausar MA, Shahid S, Anwar S, Kuddus M, Khan MKA, Khalifa AM, et al. Identifying the alpha-glucosidase inhibitory potential of dietary phytochemicals against diabetes mellitus type 2 via molecular interactions and dynamics simulation. Cellular and Molecular Biology, (2022); 67(5):16-26.

Gupta R, Brosh RMJ. Helicases as Prospective Targets for Anti-Cancer Therapy. Anti-Cancer Agents in Medicinal Chemistry. (2008); 8 (4): 390-401.

Singleton MR, Dillingham MS, Gaudier M, Kowalczykowski SC, Wigley DB. Crystal Structure of RecBCD Enzyme Reveals a Machine for Processing DNA Breaks. Nature (2004); 432 (7014): 187-193.

Itsathitphaisarn O, Wing RA, Eliason WK, Wang J, Steitz TA. The Hexameric Helicase DnaB Adopts a Nonplanar Conformation during Translocation. Cell 2012, 151 (2): 267-277.

Imanishi H, Sasaki YF, Matsumoto K, Watanabe M, Ohta T, Shirasu Y, Tutikawa K. Suppression of 6-TG-resistant mutations in V79 cells and recessive spot formations in mice by vanillin. Mutation Research, (1990); 243(2):151-8.

Das S, Roy P, Mondal S, Bera T, Mukherjee A. One pot synthesis of gold nanoparticles and application in chemotherapy of wild and resistant type visceral leishmaniasis. Colloids Surf B Biointerfaces (2013); l 1:107:27-34.

Singh PP, Chakraborty P. Malaria: autophagy as a potential therapeutic target. Journal of Pharmacy and Pharmacology, (2016); 4:298-306.




DOI: http://dx.doi.org/10.62940/als.v11i1.2343

Refbacks

  • There are currently no refbacks.