Bolaji Olawale Quadri

Conference 2024 Pre-Recorded

Talk Title

Structure-based computational design of novel covalent binders for the treatment of sickle cell disease

Authors and Affiliations

Abdeen Tunde Ogunlana 1, Ibrahim Damilare Boyenle 2, Taiwo Ooreoluwa Ojo 3,
Bolaji Olawale Quadri 3, Oluwabamise Emmanuel Elegbeleye 3, Henry Nnaemeka Ogbonna 4,
Sukurat Oluwatoyin Ayoola 5, Ibrahim Omotolase Badmus 3, Amena Khatun Manica 6,
Kehinde Isaah Joshua 2, Olubunmi Wuraola Onikute 1, Joy Perpetual Anamelechi 1,
Abayomi Odetunde 1, Adeyinka G. Falusi 1, Abdul-Quddus Kehinde Oyedele 6

1. Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria
2. Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland, USA
3. Department of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria
4. Department of Biology and Biochemistry, University of Bath, UK
5. College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria
6. Department of Chemistry, University of New Haven, West Haven, CT, USA

Abstract

Background

The quest in finding an everlasting panacea to the pernicious impact of sickle cell disease (SCD) in the society hit a turn of success since the recent discovery of a small molecule reversible covalent inhibitor, Voxelotor. A drug that primarily promotes the stability of oxygenated hemoglobin and inhibit the polymerization of HbS by enhancing hemoglobin’s affinity for oxygen has opened a new frontier in drug discovery and development. Despite eminent efforts made to reproduce small molecules with better therapeutic targets, none has been successful.

Methods

The PubChem database and DataWarrior software were used to design random molecules using Voxelotor’s electrophilic functionality. Following the compilation of these chemical entities, a high-throughput covalent docking-based virtual screening campaign was conducted. Subsequently, in silico ADMET profiling was carried out to evaluate the pharmacokinetics and pharmacodynamics properties of these compounds and their stability was evaluated for 1 μs (1 μs) using molecular dynamics simulation. Finally, to prioritize these compounds for further development in drug discovery, MM/PBSA calculations was employed to evaluate their molecular interactions and solvation energy
within the HbS protein.

Results

Covalent docking-based virtual screening revealed three (Compound_166, Compound_2301, and Compound_2335) putative druglike candidates with higher baseline energy value compared to the standard drug. ADMET profiling of these compounds revealed them to have good pharmacokinetics properties with low Toxicity and Molecular Dynamics simulation coupled with MM/PBSA calculation showcased the strong stability of their interactions.

Conclusions

Each of the three prospective drug-like candidates (Compound_166, Compound_2301 and Compound_2335) proved to be the most promising compound against the standard, Voxelotor in different sections of our computational screenings. But Despite the admirable druglike and stability properties of these compounds, further experimental validations are required to establish their preclinical relevance for drug development.