Does Size Really Matter? Probing the Efficacy of Structural Reduction in the Optimization of Bioderived Compounds – A Computational “Proof-of-Concept”

Abstract

Over the years, numerous synthetic approaches have been utilized in drug design to improve the pharmacological properties of naturally derived compounds and most importantly, minimize toxic effects associated with their transition to drugs. The reduction of complex bioderived compounds to simpler bioactive fragments has been identified as a viable strategy to develop lead compounds with improved activities and minimal toxicities. Although this ‘reductive’ strategy has been widely exemplified, underlying biological events remain unresolved, hence the unanswered question remains how does the fragmentation of a natural compound improve its bioactivity and reduce toxicities? Herein, using a combinatorial approach, we initialize a computational “proof-of- concept” to expound the differential pharmacological and antagonistic activities of a natural compound, Anguinomycin D, and its synthetic fragment, SB640 towards Exportin Chromosome Region Maintenance 1 (CRM1). Interestingly, our findings revealed that in comparison with the parent compound, SB640 exhibited improved pharmacological attributes, while toxicities and off-target activities were relatively minimal. Moreover, we observed that the reduced size of SB640 allowed ‘deep access’ at the Nuclear Export Signals (NES) binding groove of CRM1, which favored optimal and proximal positioning towards crucial residues while the presence of the long polyketide tail in Anguinomycin D constrained its burial at the hydrophobic groove. Furthermore, with regards to their antagonistic functions, structural inactivation (rigidity) was more pronounced in CRM1 when bound by SB640 as compared to Anguinomycin D. These findings provide essential insights that portray synthetic fragmentation of natural compounds as a feasible approach towards the discovery of potential leads in disease treatment.

Identification of potential SARS-CoV-2 inhibitors from South African medicinal plant extracts using molecular modelling approaches

“…Whereas hypoxoside and uzarin have a MW greater than 500 g/mol, it is important to note that natural products are usually do not adhere to the Lipinski's Rule of 5, thus inferring hypoxoside and uzarin should be further investigated for their potential anti-SARS-CoV-2 properties. Also, with their large MW, a synthetic fragmentation of their structures to smaller more simpler compounds could increases the bioactivity and decrease toxicity ( Olotu et al, 2018 ). It is also important to note that uzarin, it is currently available as an over the counter drug for gastrointestinal problems.…”

Probing the Highly Disparate Dual Inhibitory Mechanisms of Novel Quinazoline Derivatives against Mycobacterium tuberculosis Protein Kinases A and B

“…RoG has been widely employed as a parameter to determine the compactness of protein systems which in turn could be used to suggest the structural stability (or mobility) of such systems [ 48 ]. It measures atomic distribution from the center of mass, hence a high RoG could correlate with high structural instability or motion and vice versa [ 49 ]. From the estimations, high mobility characterizes the unbound NBPs of PknA and B, as supported by their relatively high FE-RoG values ( Supplementary Figure S1 ).…”

Piece of the puzzle: Remdesivir disassembles the multimeric SARS-CoV-2 RNA-dependent RNA polymerase complex

“…Relative stabilities of the SARS-CoV-2 multimers were determined by measuring the Cα-root mean square deviations (RMSDs) while other metrics such as the root mean square fluctuation (RMSF), the radius of gyration (RoG), and solvent accessibility surface area (SASA) were used to measure per-residual motions, structural compactness, and solvent-surface motions [ 31 – 33 , 39 – 41 ].…”

“…Structural insights from this study would further corroborate existing details on the therapeutic functionality of Remdesivir in its active form. Using the recently resolved crystal structure of SARS-CoV-2 RdRp-NSP12-NSP8-NSP7, we modeled the differential binding of ATP and Rem-P 3 and investigated structural events associated with the activities of both molecules using accelerated molecular dynamics (MD) simulations based on protocols used in our previous studies [ 31 – 33 ].…”