Size does not matter: a molecular insight into the biological activity of chemical fragments utilizing computational approaches.
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Insight into the functional and physiological state of a drug target is of essential importance in the drug discovery process, with the lack of emerging (3D) drug targets we propose the integration of homology modeling which may aid in the accurate yet efficient construction of 3D protein structures. In this study we present the applications of homology modeling in drug discovery, a conclusive route map and detailed technical guideline that can be utilised to obtain the most accurate model. Even with the presence of available drug targets and substantial advancements being made in the field of drug discovery, the prevalence of incurable diseases still remains at an all-time high. In this study we explore the biological activity of chemically derived fragments from natural products utilising a range of computational approaches and implement its use in a new route towards innovative drug discovery. A potential avenue referred to as the reduce to maximum concept recently proposed by organic chemists, entails reducing the size of a chemical compound to obtain a structural analogs with retained or enhanced biological activity, better synthetic approachability and reduced toxicity. Displaying that size may not in fact matter. Molecular dynamic simulations along with toxicity profiling were comparatively performed, on natural compound Anguinomycin D and its derived analog SB 640 each in complex with the CRM1 protein which plays an avid role in cancer pathogenesis. Each system was post-dynamically studied to comprehend structural dynamics adopted by the parent compound to that exhibited by the analog. Although being reduced by 60% the analog SB 640 displayed an overall exhibition of attractive pharmacophore properties which include minimal reduction in binding affinity, enhanced synthetic approachability and reduced toxicity in comparison to the parent compound. Potent inhibitor of CRM1, Leptomycin B (LMB) displayed substantial inhibition of the CRM1 export protein by binding to four of the PKIαNES residues (ϕ0, ϕ1, ϕ2, ϕ3, and ϕ4) present within the hydrophobic binding groove of CRM1. Although being drastically reduced in size and lacking the presence of the polyketide chain present in the parent compound Anguinomycin D and LMB the analog SB 640 displaced three of these essential NES residues. The potential therapeutic activity of the structural analog remains undeniable, however the application of this approach in drug design still remains ambiguous as to which chemical fragments must be retained or truncated to ensure retention or enhanced pharmacophore properties. In this study we aimed to the use of thermodynamic calculations, which was accomplished by incorporating a MM/GBSA per-residue energy contribution footprint from molecular dynamics simulation. The proposed approach was generated for each system. Anguinomycin D and analog SB 640 each in complex with CRM1 protein, each system formed interactions with the conserved active site residues Leu 536, Thr 575, Val 576 and Lys 579. These residues were highlighted as the most energetically favourable amino acid residues contributing substantially to the total binding free energy. Thus implying a conserved selectivity and binding mode adopted by both compounds despite the omission of the prominent polyketide chain in the analog SB 640, present in the parent compound. A strategic computational approach presented in this study could serve as a beneficial tool to enhance novel drug discovery. This entire work provides an invaluable contribution to the understanding of the phenomena underlying the reduction in the size of a chemical compound to obtain the most beneficial pharmacokinetic properties and could largely contribute to the design of potent analog inhibitors for a range of drug targets implicated in the orchestration of diseases.